N-(substituted-phenyl)-sulfonamide derivatives as kinase inhibitors

ABSTRACT

The invention relates to N-(substituted-phenyl)-sulfonamide compounds, which are extremely useful as inhibitors of protein kinases (e.g. PERK kinase) and accordingly can be used for the treatment of cell proliferative disorders, such as cancer, or diseases associated with activated unfolded protein response pathways, such as Alzheimer&#39;s disease. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing pharmaceutical compositions comprising these compounds.

The invention relates to N-(substituted-phenyl)-sulfonamide compounds,which are extremely useful as inhibitors of protein kinases (e.g. PERKkinase) and accordingly can be used for the treatment of cellproliferative disorders, such as cancer, or diseases associated withactivated unfolded protein response pathways, such as Alzheimer'sdisease. The present invention also provides methods for preparing thesecompounds, pharmaceutical compositions comprising these compounds, andmethods of treating diseases utilizing pharmaceutical compositionscomprising these compounds.

The endoplasmic reticulum (ER) represents the main subcellularcompartment involved in folding and maturation of proteins destined fororganelles and the extracellular space. Several kinds of stresses canalter the function of the ER, including hypoxia, alteration of proteinglycosylation, depletion of luminal ER calcium, or changes in ER redoxstatus (Wang M. and Kaufman R. J., Nat Rev Cancer. 2014 (9):581-97).These conditions provoke the accumulation of unfolded or misfoldedproteins inside the ER which culminates in the activation of a series ofadaptive mechanisms which are referred to as the Unfolded ProteinResponse (UPR) (Hetz C., Chevet E. and Harding H. P., Nat. Rev. DrugDiscov. 2013, 12, 703-719) aimed to restore protein-folding homeostasis.These include an increase in the level of chaperone proteins to favorprotein re-folding, degradation of the misfolded proteins, and arrest oftranslation to reduce the burden of proteins entering the ER. However,if cell damage is sufficiently severe or prolonged, UPR signallingresults in cell death by apoptosis (Kim I., Xu W., and Reed J. C., NatRev Drug Disc. 2008 (7):1013-1030).

The UPR is typically associated to the maintenance of cellularhomeostasis in specialized secretory cells, such as pancreatic β cells,salivary glands and plasma B cells, where the high demand for proteinsynthesis and secretion requires an efficient and tightly controlledprotein homeostasis. However, UPR is involved in many otherphysiological processes, including lipid and cholesterol metabolism,energy control, inflammation and cell differentiation (Wang M. andKaufman R. J., Nat Rev Cancer. 2014 (9):581-97). The large number ofactivities mediated by UPR reflects in the role of ER stress in theprogression of diseases such as cancer, neurodegenerative disorders anddiabetes.

In mammals, there are three classes of sensors of ER stress (Hetz C.,Chevet E. and Harding H. P., Nat. Rev. Drug Discov. 2013, 12, 703-719):inositol-requiring enzyme 1α (IRE1 or ERN1, both α and β isoforms);activating transcription factor 6 (ATF6; both α and β isoforms); andprotein kinase RNA-like ER kinase (PERK or EIF2AK3). Dimerization andautophosphorylation of IRE1α implies a conformational change thatactivates its RNase activity resulting in the excision of a26-nucleotide intron of the mRNA that encodes the transcription factorX-box binding protein 1 (XBP1). This ultimately leads to the expressionof a more stable and active form of this protein, known as XBP1s, whichtransactivates a subset of target genes involved in protein folding,ER-associated protein degradation (ERAD), protein translocation to theER, and protein secretion (Chen, Y. and Brandizzi, F. Trends Cell Biol.2013, 547-555).

ATF6α is a transmembrane protein located in the ER, which upon ERstress, translocates to the Golgi complex where it is processedreleasing a cytosolic fragment, ATF6f. This is a transcription factorthat regulates the expression of genes of the ERAD pathway (Haze, K.,Yoshida, H., Yanagi, H., Yura, T. & Mori, K., Mol. Biol. Cell 1999, 10,3787-3799).

The activation of PERK, as that of IRE1, involves dimerization,trans-autophosphorylation and the formation of large clusters. Uponactivation PERK phosphorylates eukaryotic translation initiator factor2α (eIF2α), which leads to the inhibition of protein synthesis, thusreducing the number of nascent proteins that enter the ER. This has animportant pro-survival effect on the cell perse, but, in addition, italso allows the translation of mRNAs such as that of the activatingtranscription factor 4 (ATF4), which controls the expression of genesthat encode proteins involved in redox processes and amino acidmetabolism. ATF4 also regulates the expression of important genesinvolved in apoptosis, including the transcription factorC/EBP-homologous protein (CHOP) and growth arrest and DNAdamage-inducible 34 (GADD34), which participates in a feedback loop todephosphorylate eIF2α, restoring protein synthesis. (Pytel D., MajsterekI. and Diehl J. A., Oncogene 2015 (35):1207-1215).

Tumor cells are likely to be dependent on active UPR signaling, asduring their growth they are often hypoxic and deprived of nutrient dueto insufficient blood supply and abnormal blood vessel function (RzymskiT. and Harris A. L., Clin. Cancer Res. 2007, 13(9): 2537-2540). In fact,activation of the UPR has been observed in clinical specimens. Humantumors, including those derived from cervical carcinomas, glioblastomas(Bi M., Naczki C., Koritzinsky M., Fels D., Blais J., Hu N., Harding H.,Novoa I., Varia M., Raleigh J., et al., EMBO J. 2005 (24): 3470-81),hepatocellular carcinomas (Nakagawa H., Umemura A., Taniguchi K.,Burgada J. F., Dhar D., Ogata H., Zhong Z., Valasek M. A., Seki E.,Hidalgo J., Koike K. and Kaufman R. J., Cancer Cell 2014(26): 331-343)and breast cancers (Andruska N., Zheng X., Yang X., Helferich W. G., andShapiro D. J., Oncogene 2015, 34(29): 3760-3769), show levels ofproteins involved in UPR higher than in normal tissues, possiblyindicating a stronger dependence of cancer cells on protein homeostasisand functional ER in order to survive.

Besides, aberrant activation of the unfolded protein response isinvolved in a wide variety of other pathologies, such as oculardiseases, obesity, diabetes (e.g. type 1 diabetes), stroke, myocardialinfarction, cardiovascular disease, atherosclerosis, arrhythmias, viralinfections, inflammatory diseases, neurodegenerative diseases (such asprion-related diseases, amyotrophic lateral sclerosis, Alzheimer's,Huntington's and Parkinson's disease), and the like. (Wang M. andKaufman R. J., Nature 2016(529):326-335). Therefore, inhibition of theUPR with small molecules capable of blocking the activity of PERK andother components of the UPR will result in an anticancer effect, as wellas in the possibility to treat diseases where there is an activatedunfolded protein response.

SUMMARY OF THE INVENTION

Three examples of classes of compounds inhibitors of PERK arerepresented by the substituted indoline derivatives disclosed inapplication WO2011/119663 and the substituted pyrrolidinone derivativesdisclosed in application WO2015/136463, both in the name ofGlaxosmithkline LLC, and the substituted quinazolamine derivativesdisclosed in application WO2014/161808 in the name of JanssenPharmaceutica NV.

Novel classes of pyrrolo[2,3d]pyrimidines and 4-aminopyrrolopyrimidines,useful as serine/threonine or tyrosine kinase inhibitors, arerespectively disclosed in WO98/41525 in the name of Knoll AG andWO00/17202 in the name of Basf AG.

Other kinase inhibitors represented by fused ring heteroaryl compoundsare described in WO2010/045542 in the name of The Regents of theUniversity of California.

However, there is a strong need for novel compounds which inhibit PERKkinase activity useful for the treatment or prevention of cancer, inparticular secretory cancer types, neurodegenerative diseases (such asamyotrophic lateral sclerosis, prion-related diseases, Huntington's,Alzheimer's and Parkinson's disease), and the like, as well as diabetes,obesity, ocular diseases, stroke, myocardial infarction, cardiovasculardisease, atherosclerosis, arrhythmias, viral infectious and inflammatorydiseases. It is accordingly an object of the present invention toprovide such compounds.

DETAILED DESCRIPTION OF THE INVENTION

The present inventors have now discovered that compounds of formula (I),described below, are kinase inhibitors and in particular are inhibitorsof PERK, and therefore, are useful in therapy as antitumor agents.

Accordingly, a first object of the present invention is to provide anN-(substituted-phenyl)-sulfonamide represented by formula (I),

wherein:n is 0, 1 or 2;R1 is an optionally substituted group selected from straight or branched(C₁-C₈) alkyl, (C₂-C₈) alkenyl, (C₂-C₈) alkynyl, (C₃-C₈) cycloalkyl,(C₃-C₈) cycloalkenyl, heterocyclyl, aryl and heteroaryl;R2 and R3 are independently halogen, cyano, OR4 or an optionallysubstituted group selected from straight or branched (C₁-C₈) alkyl,(C₂-C₈) alkenyl, (C₂-C₈) alkynyl and (C₃-C₈) cycloalkyl, wherein

-   -   R4 is an optionally substituted group selected from straight or        branched (C₁-C₈) alkyl, (C₂-C₈) alkenyl, (C₂-C₈) alkynyl and        (C₃-C₈) cycloalkyl;        E₁ and E₂ are independently CH or N;        A is O, S or NR5, wherein    -   R5 is hydrogen or an optionally substituted group selected from        straight or branched (C₁-C₈) alkyl, (C₂-C₈) alkenyl, (C₂-C₈)        alkynyl, (C₃-C₈) cycloalkyl, (C₃-C₈) cycloalkenyl, heterocyclyl,        aryl and heteroaryl;        and tautomers, hydrates, solvates, N-oxides and pharmaceutically        acceptable salts thereof.

The present invention also provides methods of preparing theN-(substituted-phenyl)-sulfonamide compounds represented by formula (I),prepared through a process consisting of standard synthetictransformations.

The present invention also provides a method for treating diseasescaused by and/or associated with dysregulated protein kinase activity,particularly protein kinase RNA-like ER kinase (PERK or EIF2AK3) whichcomprises administering to a mammal, in need thereof, an effectiveamount of an N-(substituted-phenyl)-sulfonamide compound represented byformula (I) as defined above.

A preferred method of the present invention is to treat a disease causedby and/or associated with dysregulated protein kinase activity selectedfrom the group consisting of cancer, cell proliferative disorders, viralinfections, autoimmune and neurodegenerative disorders.

Another preferred method of the present invention is to treat specifictypes of cancer including but not limited to: carcinoma, includingbladder, breast, colon, kidney, liver, lung, including small cell lungcancer, esophagus, gall-bladder, ovary, pancreas, stomach, cervix,thyroid, prostate, and skin, including squamous cell carcinoma;hematopoietic tumors of lymphoid lineage including leukaemia, acutelymphocitic leukaemia, acute lymphoblastic leukaemia, B-cell lymphoma,T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy celllymphoma and Burkett's lymphoma; hematopoietic tumors of myeloidlineage, including acute and chronic myelogenous leukemias,myelodysplastic syndrome and promyelocytic leukaemia; tumors ofmesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumorsof the central and peripheral nervous system, including astrocytomaneuroblastoma, glioma and schwannomas; other tumors, including melanoma,seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum,keratoxanthoma, thyroid follicular cancer and Kaposi's sarcoma.

In addition, the method of the present invention provides tumorangiogenesis and metastasis inhibition as well as the treatment of organtransplant rejection and host versus graft disease.

Another preferred method of the present invention is to treat specificcellular proliferative disorders such as, for example, benign prostatehyperplasia, familial adenomatosis polyposis, neurofibromatosis,psoriasis, vascular smooth cell proliferation associated withatherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis andpost-surgical stenosis and restenosis.

Another preferred method of the present invention is to treat viralinfections, in particular the prevention of AIDS development inHIV-infected individuals.

Another preferred method of the present invention is to treat autoimmuneand neurodegenerative diseases, in particular transplant rejection, skindisorders including psoriasis, allergies, asthma, rheumatoid arthritis(RA), multiple sclerosis, systemic lupus erythematosus (SLE), Crohn'sdisease, prion-related diseases, Alzheimer's disease, degenerative nervediseases, encephalitis, stroke, Parkinson's disease, amyotrophic lateralsclerosis, Huntington's disease and Pick's disease.

Another preferred method of the present invention is to treatAlzheimer's disease, which comprises administering to a subject in needthereof an effective amount of a compound of Formula (I).

Another preferred method of the present invention is to treat stroke,which comprises administering to a subject in need thereof an effectiveamount of a compound of Formula (I).

Another preferred method of the present invention is to treat Type 1diabetes, which comprises administering to a subject in need thereof aneffective amount of a compound of Formula (I).

Another preferred method of the present invention is to treat a diseasestate selected from: myocardial infarction, cardiovascular disease,atherosclerosis, arrhythmias, obesity, ocular diseases and inflammatorydiseases, which comprises administering to a subject in need thereof aneffective amount of a compound of Formula (I).

Moreover, the method of the present invention further comprisessubjecting the mammal in need thereof to a radiation therapy orchemotherapy regimen in combination with at least one cytostatic orcytotoxic agent.

The present invention also provides a pharmaceutical compositioncomprising one or more compounds of formula (I) or a pharmaceuticallyacceptable salt thereof, as defined above, and at least onepharmaceutically acceptable excipient, carrier or diluent.

The present invention further provides a pharmaceutical compositioncomprising a compound of formula (I) further comprising one or morechemotherapeutic—e.g. cytostatic or cytotoxic—agents, antibiotic-typeagents, alkylating agents, antimetabolite agents, hormonal agents,immunological agents, interferon-type agents, cyclooxygenase inhibitors(e.g. COX-2 inhibitors), matrixmetalloprotease inhibitors, telomeraseinhibitors, tyrosine kinase inhibitors, anti-growth factor receptoragents, anti-HER agents, anti-EGFR agents, anti-angiogenesis agents(e.g. angiogenesis inhibitors), farnesyl transferase inhibitors, ras-rafsignal transduction pathway inhibitors, cell cycle inhibitors, cdksinhibitors, tubulin binding agents, topoisomerase I inhibitors,topoisomerase II inhibitors, and the like.

Moreover the invention provides an in vitro method for inhibiting theprotein kinase RNA-like ER kinase (PERK or EIF2AK3) activity whichcomprises contacting the said protein with an effective amount of acompound of formula (I) as defined above.

Additionally, the invention provides a product comprising a compound offormula (I) or a pharmaceutically acceptable salt thereof, as definedabove, and one or more chemotherapeutic agents, as a combinedpreparation for simultaneous, separate or sequential use in anticancertherapy.

In yet another aspect the invention provides a compound of formula (I)or a pharmaceutically acceptable salt thereof, as defined above, for useas a medicament.

Moreover the invention provides a compound of formula (I) or apharmaceutically acceptable salt thereof, as defined above, for use in amethod of treating cancer.

Finally, the invention provides the use of a compound of formula (I) ora pharmaceutically acceptable salt thereof, as defined above, in themanufacture of a medicament with anticancer activity.

Unless otherwise specified, when referring to the compounds of formula(I) per se as well as to any pharmaceutical composition thereof or toany therapeutic treatment comprising them, the present inventionincludes all of the hydrates, solvates, complexes, metabolites,prodrugs, carriers, N-oxides and pharmaceutically acceptable salts ofthe compounds of this invention.

A metabolite of a compound of formula (I) is any compound into whichthis same compound of formula (I) is converted in vivo, for instanceupon administration to a mammal in need thereof. Typically, withouthowever representing a limiting example, upon administration of acompound of formula (I), this same derivative may be converted into avariety of compounds, for instance including more soluble derivativeslike hydroxylated derivatives, which are easily excreted. Hence,depending upon the metabolic pathway thus occurring, any of thesehydroxylated derivatives may be regarded as a metabolite of thecompounds of formula (I).

Prodrugs are any covalently bonded compounds, which release in vivo theactive parent drug according to formula (I).

N-oxides are compounds of formula (I) wherein nitrogen and oxigen aretethered through a dative bond.

If a chiral center or another form of an isomeric center is present in acompound of the present invention, all forms of such isomer or isomers,including enantiomers and diastereomers, are intended to be coveredherein. Compounds containing a chiral center may be used as a racemicmixture, an enantiomerically enriched mixture, or the racemic mixturemay be separated using well-known techniques and an individualenantiomer may be used alone. In cases in which compounds haveunsaturated carbon-carbon double bonds, both the cis (Z) and trans (E)isomers are within the scope of this invention.

In cases when compounds can exist in tautomeric forms, each form iscontemplated as being included within this invention whether existing inequilibrium or predominantly in one form.

As such, unless otherwise provided, when in compounds of formula (I) E₂is nitrogen, A is NR5 and R5 is hydrogen, only one of the followingtautomeric forms of formula (Ia) or (Ib) is indicated, the remaining onehas still to be intended as comprised within the scope of the invention:

In cases wherein compounds may exist in other tautomeric forms, such asketo-enol tautomers, each tautomeric form is contemplated as beingincluded within this invention whether existing in equilibrium orpredominantly in one form.

With the term “straight or branched (C₁-C₈) alkyl”, we intend any of thegroups such as, for instance, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, n-hexyl, and thelike.

With the term “(C₃-C₈) cycloalkyl” we intend, unless otherwise provided,3- to 8-membered all-carbon monocyclic ring, which may contain one ormore double bonds but does not have a completely conjugated π-electronsystem. Examples of cycloalkyl groups, without limitation, arecyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane,cyclohexene and cyclohexadiene.

With the term “heterocyclyl” we intend a 3- to 7-membered, saturated orpartially unsaturated carbocyclic ring where one or more carbon atomsare replaced by heteroatoms such as nitrogen, oxygen and sulfur. Nonlimiting examples of heterocyclyl groups are, for instance, pyrane,pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine,pyrazoline, thiazoline, thiazolidine, dihydrofuran, tetrahydrofuran,1,3-dioxolane, piperidine, piperazine, morpholine and the like. Theheterocyclyl ring can be optionally further fused or linked to aromaticand non-aromatic carbocyclic and heterocyclic rings.

With the term “(C₂-C₈) alkenyl” we intend an aliphatic (C₂-C₈)hydrocarbon chain containing at least one carbon-carbon double bond andwhich can be straight or branched. Representative examples include, butare not limited to, ethenyl, 1-propenyl, 2-propenyl, 1- or 2-butenyl,and the like.

With the term “(C₂-C₈) alkynyl” we intend an aliphatic (C₂-C₈)hydrocarbon chain containing at least one carbon-carbon triple bond andwhich can be straight or branched. Representative examples include, butare not limited to, ethynyl, 1-propynyl, 2-propynyl, 1- or 2-butynyl,and the like.

The term “aryl” refers to a mono-, bi- or poly-carbocyclic hydrocarbonwith from 1 to 4 ring systems, optionally further fused or linked toeach other by single bonds, wherein at least one of the carbocyclicrings is “aromatic”, wherein the term “aromatic” refers to completelyconjugated π-electron bond system. Non limiting examples of such arylgroups are phenyl, α- or β-naphthyl or biphenyl groups.

The term “heteroaryl” refers to aromatic heterocyclic rings, typically5- to 7-membered heterocycles with from 1 to 3 heteroatoms selectedamong N, O or S; the heteroaryl ring can be optionally further fused orlinked to aromatic and non-aromatic carbocyclic and heterocyclic rings.Not limiting examples of such heteroaryl groups are, for instance,pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl,thiazolyl, isothiazolyl, pyrrolyl, phenyl-pyrrolyl, furyl, phenyl-furyl,oxazolyl, isoxazolyl, pyrazolyl, thienyl, benzothienyl, isoindolinyl,benzoimidazolyl, quinolinyl, isoquinolinyl, 1,2,3-triazolyl,1-phenyl-1,2,3-triazolyl, 2,3-dihydroindolyl, 2,3-dihydrobenzofuranyl,2,3-dihydrobenzothiophenyl, benzopyranyl, 2,3-dihydrobenzoxazinyl,2,3-dihydroquinoxalinyl and the like.

According to the present invention and unless otherwise provided, any ofthe above R1, R2, R3, R4 and R5 group may be optionally substituted, inany of their free positions, by one or more groups, for instance 1 to 6groups, independently selected from: halogen, nitro, oxo groups (═O),cyano, (C₁-C₈) alkyl, polyfluorinated (C₁-C₈) alkyl, polyfluorinated(C₁-C₈) alkoxy, (C₂-C₈) alkenyl, (C₂-C₈) alkynyl, hydroxyalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl,(C₃-C₈) cycloalkyl, hydroxy, (C₁-C₈) alkoxy, aryloxy, heterocyclyloxy,methylenedioxy, alkylcarbonyloxy, arylcarbonyloxy, cycloalkenyloxy,heterocyclylcarbonyloxy, alkylideneaminooxy, carboxy, alkoxycarbonyl,aryloxycarbonyl, cycloalkyloxycarbonyl,heterocyclylalkyloxycarbonyl-amino, ureido, alkylamino, dialkylamino,arylamino, diarylamino, heterocyclylamino, formylamino,alkylcarbonylamino, arylcarbonylamino, heterocyclylcarbonylamino,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, heterocyclylaminocarbonyl, alkoxycarbonylamino,hydroxyaminocarbonyl alkoxyimino, alkylsulfonylamino, arylsulfonylamino,heterocyclylsulfonylamino, formyl, alkylcarbonyl, arylcarbonyl,cycloalkylcarbonyl, heterocyclylcarbonyl, alkylsulfonyl, arylsulfonyl,aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,arylaminosulfonyl, heterocyclylaminosulfonyl, arylthio, alkylthio,phosphonate and alkylphosphonate. In their turn, whenever appropriate,each of the above substituent may be further substituted by one or moreof the aforementioned groups.

With the term halogen atom we intend a fluorine, chlorine, bromine oriodine atom.

With the term cyano we intend a —CN residue.

With the term nitro we intend a —NO₂ group.

With the term polyfluorinated alkyl or polyfluorinated alkoxy we intendany of the above straight or branched (C₁-C₈) alkyl or alkoxy groupswhich are substituted by more than one fluorine atom such as, forinstance, trifluoromethyl, trifluoroethyl, 1,1,1,3,3,3-hexafluoropropyl,trifluoromethoxy and the like.

With the term hydroxyalkyl we intend any of the above (C₁-C₈) alkyl,bearing an hydroxyl group such as, for instance, hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl and the like.

From all of the above, it is clear to the skilled person that any groupwhich name is a composite name such as, for instance, arylamino has tobe intended as conventionally construed by the parts from which itderives, e.g. by an amino group which is further substituted by aryl,wherein aryl is as above defined.

Likewise, any of the terms such as, for instance, alkylthio, alkylamino,dialkylamino, alkoxycarbonyl, alkoxycarbonylamino, heterocyclylcarbonyl,heterocyclylcarbonylamino, cycloalkyloxycarbonyl and the like, includegroups wherein the alkyl, alkoxy, aryl, cycloalkyl and heterocyclylmoieties are as above defined.

Pharmaceutically acceptable salts of the compounds of formula (I)include the acid addition salts with inorganic or organic acids, e.g.,nitric, hydrochloric, hydrobromic, sulfuric, perchloric, phosphoric,acetic, trifluoroacetic, propionic, glycolic, lactic, oxalic, malonic,malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic,methanesulphonic, isethionic and salicylic acid.

Pharmaceutically acceptable salts of the compounds of formula (I) alsoinclude the salts with inorganic or organic bases, e.g., alkali oralkaline-earth metals, especially sodium, potassium, calcium ammonium ormagnesium hydroxides, carbonates or bicarbonates, acyclic or cyclicamines.

Preferably, object of the present invention are compounds of formula (I)wherein n is 0 or 1; R1 is an optionally substituted group selected from(C₃-C₈) cycloalkyl, aryl and heteroaryl; R2 is halogen or (C₁-C₈) alkyl;A is S or NR5 and R3, R4, E₁, E₂ and R5 are as defined above.

More preferably, object of the present invention are compounds offormula (I) wherein n is 0; R1 is an optionally substituted aryl orheteroaryl; R2 is halogen; A is NR5 and R3, R4, E₁, E₂ and R5 are asdefined above.

Even more preferably, object of the present invention are compounds offormula (I) wherein n is 0; R1 is an optionally substituted aryl; R2 ishalogen; E₁ is N; E₂ is CH; A is NR5, wherein R5 is an optionallysubstituted group selected from straight or branched (C₁-C₈) alkyl and(C₃-C₈) cycloalkyl; and R3 and R4 are as defined above.

Specific, not limiting, preferred compounds (cmpds.) of the invention,whenever appropriate in the form of pharmaceutically acceptable salts,are the following:

-   1)    N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-3-chloro-4-methoxy-benzenesulfonamide    (cmpd 1);-   2)    N-[3-(4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-3-chloro-4-methoxy-benzenesulfonamide    (cmpd 2);-   3)    N-{3-[4-Amino-7-(1-methyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-5-chloro-2-fluoro-4-methoxy-benzenesulfonamide    (cmpd 3);-   4)    N-{3-[4-Amino-7-(1-methyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-3-chloro-4-methoxy-benzenesulfonamide    (cmpd 4);-   5)    N-{3-[4-Amino-7-(1-cyclopropyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-3-chloro-4-methoxy-benzenesulfonamide    (cmpd 5);-   6)    N-{3-[4-Amino-7-(1-isopropyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-3-chloro-4-methoxy-benzenesulfonamide    (cmpd 6);-   7)    N-[3-(4-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenyl]-5-chloro-2-fluoro-4-methoxy-benzenesulfonamide    (cmpd 9);-   8)    N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-4-methoxy-3-methyl-benzenesulfonamide    (cmpd 12);-   9)    N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-3-chloro-benzenesulfonamide    (cmpd 13);-   10)    N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-4-bromo-2-fluoro-benzenesulfonamide    (cmpd 22);-   11)    N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-5-chloro-2-fluoro-4-methoxy-benzenesulfonamide    (cmpd 24);-   12)    N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-3,4-dichloro-benzenesulfonamide    (cmpd 25);-   13)    N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-3,5-dichloro-benzenesulfonamide    (cmpd 26);-   14)    N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-4-methoxy-3,5-dimethyl-benzenesulfonamide    (cmpd 29);-   15)    N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-3,4,5-trifluoro-benzenesulfonamide    (cmpd 32);-   16) 5-Bromo-6-chloro-pyridine-3-sulfonic acid    [3-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-amide    (cmpd 33);-   17)    N-[3-(4-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenyl]-4-methoxy-3-methyl-benzenesulfonamide    (cmpd 34);-   18)    N-[3-(4-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenyl]-3-chloro-4-methoxy-benzenesulfonamide    (cmpd 35);-   19)    N-{3-[4-Amino-7-(tetrahydro-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-4-methoxy-3-methyl-benzenesulfonamide    (cmpd 36);-   20)    N-{3-[4-Amino-7-(tetrahydro-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-3-chloro-4-methoxy-benzenesulfonamide    (cmpd 37);-   21)    N-{3-[4-Amino-7-(1-methyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-4-methoxy-3-methyl-benzenesulfonamide    (cmpd 38);-   22)    N-{3-[4-Amino-7-(1-cyclopropyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-4-methoxy-3-methyl-benzenesulfonamide    (cmpd 39);-   23)    N-{3-[4-Amino-7-(1-isopropyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-4-methoxy-3-methyl-benzenesulfonamide    (cmpd 40);-   24)    N-{3-[4-Amino-7-(1-ethyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-4-methoxy-3-methyl-benzenesulfonamide    (cmpd 41);-   25)    N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-2-fluoro-4-methoxy-5-methyl-benzenesulfonamide    (cmpd 44);-   26)    N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-4-bromo-2,5-difluoro-benzenesulfonamide    (cmpd 46);-   27) 5-Chloro-thiophene-2-sulfonic acid    [3-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-amide    (cmpd 47);-   28) 5-Bromo-thiophene-2-sulfonic acid    [3-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-amide    (cmpd 48);-   29)    N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-4-bromo-3-methyl-benzenesulfonamide    (cmpd 52);-   30)    N-{3-[4-Amino-1-(1-methyl-piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl}-5-chloro-2-fluoro-4-methoxy-benzenesulfonamide    (cmpd 61);-   31)    N-[3-(4-Amino-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenyl]-5-chloro-2-fluoro-4-methoxy-benzenesulfonamide    (cmpd 62);-   32)    N-[3-(4-Amino-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenyl]-3-chloro-4-methoxy-benzenesulfonamide    (cmpd 63);-   33)    N-[3-(4-Amino-7-piperidin-4-yl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-4-methoxy-3-methyl-benzenesulfonamide    (cmpd 64);-   34)    N-{3-[4-Amino-7-(1-methyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-3,4-dichloro-benzenesulfonamide    (cmpd 71);-   35)    N-{3-[4-Amino-7-(1-methyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-4-bromo-2-fluoro-benzenesulfonamide    (cmpd 72);-   36)    N-{3-[4-Amino-7-(1-methyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-2-fluoro-4-methoxy-5-methyl-benzenesulfonamide    (cmpd 73);-   37) 6-Methoxy-pyridine-3-sulfonic acid    [3-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-amide    (cmpd 81);-   38)    N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-4-chloro-2-fluoro-benzenesulfonamide    (cmpd 85) and-   39)    N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-3-bromo-4-methoxy-benzenesulfonamide    (cmpd 87).

The present invention also provides a process for the preparation of acompound of formula (I) as defined above, by using the reaction routesand synthetic schemes described below, employing the techniquesavailable in the art and starting materials readily available. Thepreparation of certain embodiments of the present invention is describedin the examples that follow, but those of ordinary skill in the art willrecognize that the preparations described may be readily adapted toprepare other embodiments of the present invention. For example, thesynthesis on non-examplified compounds according to the invention may beperformed by modifications apparent to those skilled in the art, forinstance by appropriately protecting interfering groups, by changing toother suitable reagents known in the art, or by making routinemodifications of reaction conditions. Alternatively other reactionsreferred to herein or known in the art will be recognized as havingadaptability for preparing other compounds of the invention.

In one general synthetic process, compounds of formula (I) as definedabove can be prepared according to the following Scheme 1:

In the above scheme 1 A, E₁, E₂, R1, R2, R3 and n are as defined above;X is a halogen atom, such as iodine or bromine, or a suitable leavinggroup, such as triflate; M is a suitable organometal group, such asB(OH)₂, B(OAlk)₂, Sn(Alk)₃, Al(Alk)₂, ZnX, MgX or ZrCp₂X, wherein X ishalogen and Alk is a (C₁-C₈) alkyl, and Pg is a suitable nitrogenprotecting group, such as tertbutoxy carbonyl, benzyl,benzyloxycarbonyl, methoxymethyl or the like.

In a synthetic process for the preparation of a compound of formula (I),which is described in scheme 1, in step “a” a compound of formula (kind)is reacted with a compound of formula (IV) exploiting any of thecross-coupling reactions suitable for the formation of carbon-carbonbonds. Said reactions, which are well known in the art, imply couplingwith a suitable organometal reagent, such as, for instance, anorganoboron, organotin, organozinc, organoalluminum or organozirconiumcompound and the like. In step “b” the same kind of reaction may beperformed to couple a compound of formula (II) with a compound offormula (VI) to yield a compound of formula (VII). In step “c” the samekind of reaction may be performed to couple a compound of formula (II)with a compound of formula (VIII) to yield a compound of formula (I). Instep “d” the same kind of reaction may be performed to couple a compoundof formula (II) with a compound of formula (IX) to yield a compound offormula (X). In step “e” a compound of formula (V) undergoes selectiveremoval of the group Pg to give a compound of formula (VII), which, instep “f”, is reacted with a sulfonyl chloride derivative of formula (XI)to yield a compound of formula (I). In step “g” selective removal of theprotecting group from a compound of formula (X) yields a compound offormula (I).

In step “a1” a compound of formula (III) is reacted with a compound offormula (IV) exploiting any of the cross-coupling reactions suitable forthe formation of carbon-carbon bonds as reported above for step “a” toform a compound of formula (XII). In step “b1” the same kind of reactionmay be performed to couple a compound of formula (III) with a compoundof formula (VI) to yield a compound of formula (XIII). In step “c1” thesame kind of reaction may be performed to couple a compound of formula(III) with a compound of formula (VIII) to yield a compound of formula(XIV). In step “d1” the same kind of reaction may be performed to couplea compound of formula (III) with a compound of formula (IX) to yield acompound of formula (XV). In step “e1” a compound of formula (XII)undergoes selective removal of the group Pg to give a compound offormula (XIII), which, in step “f1”, is reacted with a sulfonyl chloridederivative of formula (XI) to yield a compound of formula (XIV). In step“g1” selective removal of the protecting group from a compound offormula (XV) yields a compound of formula (XIV).

In step “h” the reaction of a compound of formula (XV) with ammonia oran ammonia equivalent, such as ammonium acetate, affords a compound ofgeneral formula (X). In step “h1” the same kind of reaction performed ona compound of formula (XIV) yields a compound of formula (I). In step“h2” the same kind of reaction performed on a compound of formula (XIII)yields a compound of formula (VII). In step “h3” the same kind ofreaction performed on a compound of formula (XII) yields a compound offormula (V).

According to step “a” of scheme 1, a compound of formula (II) is reactedwith a suitable organometal derivative of formula (IV), such as, forinstance, an organoboron compound (Suzuki reaction), an organotincompound (Stille reaction), an organozinc, organoalluminium ororganozirconium compound (Negishi reaction), and the like. Saidreactions are well known among those with ordinary skills in the art.Preferred reaction is the Suzuki reaction where an appropriate aryl orheteroaryl boronate ester or acid is used in the presence of a palladiumor nickel-based catalyst, such as, for instance,palladium(tetrakistriphenyl)phosphine, and a suitable base, such asCs₂CO₃, K₂CO₃, Rb₂CO₃, NaOH, CsF, and the like. Said reactions can becarried out in a solvent such as N,N-dimethylformamide,dimethylsulfoxide, water, dimethoxyethane, 1,4-dioxane, tetrahydrofuranor the like, and mixtures thereof, in a microwaves apparatus or in theclassical thermal conditions, at a temperature ranging from 90 to 120°C. and for a time ranging from 30 minutes to about 24 hours.

According to steps “b”, “c” and “d” of scheme 1, a compound of formula(II) is transformed into a compound respectively of formula (VII), (I)and (X) as defined above, by means of a cross-coupling reaction with aderivative respectively of formula (VI), (VIII) and (IX) as definedabove according to step “a” of scheme 1.

According to step “e” or “g” of scheme 1, the selective removal of thePg group, respectively from a compound of formula (V) to afford acompound of formula (VII) or from a compound of formula (X) to afford acompound of formula (I), can be accomplished using acidic or reductiveconditions. For instance, the reaction is carried out using strongacids, such as trifluoroacetic acid, optionally in the presence ofsuitable co-solvent, such as dichloromethane, at temperatures rangingfrom 20° C. to reflux and for a time ranging from 30 minutes to about 48hours. Alternatively, when Pg is a benzyl or a benzyloxy group, saidreaction is carried out using reductive conditions, such H₂ in thepresence of a suitable hydrogenation catalyst. The hydrogenationcatalyst is usually a metal, most often palladium, which can be used assuch or supported on carbon, in a suitable solvent such as, forinstance, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, methanol,ethyl acetate, or a mixture thereof.

According to step “f” of scheme 1, a compound of formula (VII) isreacted with a sulfonyl chloride of formula (XI) to afford a compound offormula (I). Such a reaction is carried out in the presence of asuitable base, such as for instance pyridine, N-methyl morpholine ordiisopropyl ethylamine, in the appropriate solvent such as pyridine,dichloromethane or tetrahydrofuran, at a temperature ranging from 0° C.to reflux and for a time varying from about 1 hour to about 7 days.

According to steps “a1”, “b1”, “c1” and “d1” of scheme 1, the conversionof a compound of formula (III) into a compound respectively of formula(XII), (XIII), (XIV) and (XV) is accomplished as described under step“a” of scheme 1.

According to steps “e1” and “g1” of scheme 1, the conversion of acompound of formula (XII) and (XV) respectively into a compound formula(XIII) and (XIV) is accomplished as described under step “e” of scheme1.

According to step “f1” of scheme 1, the conversion of a compound offormula (XIII) into a compound of formula (XIV) is accomplished asdescribed under step “f” of scheme 1.

According to step “h” of scheme 1, a compound of formula (XV) istransformed into a compound of formula (X) using a solution of ammoniain a suitable solvent, such as tetrahydrofuran, 1,4-dioxane, pyridine,methanol, ethanol and the like, or ammonium salts, such as for instanceammonium acetate or ammonium hydrochloride in solvents such as water,N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl pyrrolidone,dimethylsulfoxide and the like and mixture thereof, at temperaturesranging from 20° C. to reflux in the classical thermal conditions orusing a microwaves apparatus for a time ranging from 30 minutes to about24 hours.

According to steps “h1”, “h2” and “h3” of scheme 1, a compound offormula (XIV), (XIII) and (XII) is converted respectively into acompound of formula (I), (VII) and (V) as described under step “h” ofscheme 1.

Preferably, compounds of formula (I) or pharmaceutically acceptablesalts thereof, as defined above, can be prepared according to theprocess defined above, comprising the step of cross-coupling of anintermediate of formula (II)

wherein E₁, E₂, A are as defined in claim 1 and X is halogen or aleaving group, alternatively with the following compounds:

Step a) a derivative of formula (IV)

wherein R2, R3 and n are as defined above, M is an organometal group andPg is a nitrogen protecting group; followed by

Step e) selective removing of the Pg group from the resultantintermediate of formula (V)

-   -   wherein E₁, E₂, A, R2, R3, n and Pg are as defined above; and

Step f) reacting the resultant intermediate of formula (VII)

-   -   wherein E₁, E₂, A, R2, R3 and n are as defined above, with a        derivative of formula (XI)

-   -   wherein R1 is as defined above, to obtain a compound of        formula (I) as defined above;

OR:

Step b) a derivative of formula (VI)

wherein R2, R3, n and M are as defined above; followed by

Step f) reacting the resultant intermediate of formula (VII), as definedabove, with a derivative of formula (XI),

-   -   as defined above, to obtain a compound of formula (I) as defined        above;

OR:

Step c) a derivative of formula (VIII)

-   -   wherein R1, R2, R3, n and M are as defined above;

OR:

Step d) a derivative of formula (IX)

wherein R1, R2, R3, n, Pg and M are as defined above; followed by:

Step g) selective removing of the Pg group from the resultantintermediate of formula (X)

-   -   wherein E₁, E₂, A, R1, R2, R3, n and Pg are as defined above, to        obtain a compound of formula (I) as defined above;        optionally converting a compound of formula (I) into another        compound of formula (I), and, if desired, converting a compound        of formula (I) into a pharmaceutically acceptable salt thereof        or converting a salt into the free compound (I).

Alternatively, a compound of formula (I) as defined above can beprepared according to the following Scheme 2:

In the above scheme 2 A, E₁, E₂, R1, R2, R3, n, X, M and Pg are asdefined above.

In a synthetic process for the preparation of a compound of formula (I),which is described in scheme 2, in steps “a2”, “b2”, “c2”, or “d2” acompound of formula (XVI) is respectively reacted with a compound offormula (XVIII), (XIX), (XX), or (XXI) exploiting any of thecross-coupling reactions suitable for the formation of carbon-carbonbonds to yield respectively compounds of formula (V), (VII), (I), or(X). In step “e” a compound of formula (V) undergoes selective removalof the group Pg to give a compound of formula (VII), which, in step “f”,is reacted with a sulfonyl chloride derivative of formula (XI) to yielda compound of formula (I). In step “g” selective removal of theprotecting group from a compound of formula (X) yields a compound offormula (I).

In steps “a3”, “b3”, “c3”, or “d3” a compound of formula (XVII) isrespectively reacted with a compound of formula (XVIII), (XIX), (XX), or(XXI) exploiting any of the cross-coupling reactions suitable for theformation of carbon-carbon bonds to yield respectively compounds offormula (XII), (XIII), (XIV), or (XV). In step “e1” a compound offormula (XII) undergoes selective removal of the group Pg to give acompound of formula (XIII), which, in step “f1”, is reacted with asulfonyl chloride derivative of formula (XI) to yield a compound offormula (XIV). In step “g1” selective removal of the protecting groupfrom a compound of formula (XV) yields a compound of formula (XIV).

In step “h” the reaction of a compound of formula (XV) with ammonia oran ammonia equivalent such as ammonium acetate, affords a compound ofgeneral formula (X). In step “h1” the same kind of reaction performed ona compound of formula (XIV) yields a compound of formula (I). In step“h2” the same kind of reaction performed on a compound of formula (XIII)yields a compound of formula (VII). In step “h3” the same kind ofreaction performed on a compound of formula (XII) yields a compound offormula (V),

According to steps “a2”, “b2”, “c2” and “d2” of scheme 2, the conversionof a compound of formula (XVI) into a compound respectively of formula(V), (VII), (I) and (X) is accomplished as described under step “a” ofscheme 1.

According to steps “e” and “g” of scheme 2, the conversion of a compoundof formula (V) and (X) respectively into a compound formula (VII) and(I) is accomplished as described under step “e” of scheme 1.

According to step “f” of scheme 2, the conversion of a compound offormula (VII) into a compound formula (I) is accomplished as describedunder step “f” of scheme 1.

According to steps “a3”, “b3”, “c3” and “d3” of scheme 2, the conversionof a compound of formula (XVII) into a compound respectively of formula(XII), (XIII), (XIV) and (XV) is accomplished as described under step“a” of scheme 1.

According to steps “e1” and “g1” of scheme 2, the conversion of acompound of formula (XII) and (XV) into a compound respectively offormula (XIII) and (XIV) is accomplished as described under step “e” ofscheme 1.

According to step “f1” of scheme 2, the conversion of a compound offormula (XIII) into a compound of formula (XIV) is accomplished asdescribed under step “f” of scheme 1.

According to steps “h”, “h1”, “h2” and “h3” of scheme 2, the conversionof a compound of formula (XV), (XIV), (XIII) and (XII) into a compoundrespectively of formula (X), (I), (VII) and (V) is accomplished asdescribed under step “h” of scheme 1.

Alternatively, a compound of formula (II)A wherein X, E₁ and E₂ are asdefined above and A is N—R5, wherein R5 is as defined above, can beprepared according to the following scheme 3:

In the above scheme 3 A, E₁, E₂, R1, R2, R3, n, X, M are as definedabove and L is OH or a group that may work as a leaving group, such as ahalogen atom, a tosylate, mesylate or triflate, or L is a group —B(OH)₂.

In a synthetic process for the preparation of a compound of formula (II)A which is described in scheme 3, in step “h5” the reaction of acompound of formula (III) with ammonia or an ammonia equivalent, affordsa compound of general formula (II). When A is a group NH, in step “l”N-alkylation with a suitable alkylating agent of formula L-R5, affords acompound of formula (II)A. Alternatively, when A is a group NH, in step“l1” N-alkylation of a compound of formula (III) with a suitablealkylating agent of formula L-R5, affords a compound of formula (III)A.In step “h5A” such a compound of formula (III)A is treated with ammoniaor an ammonia equivalent to afford a compound of general formula (II)A.In step “i” a compound of formula (II) is converted into an organometalderivative of formula (XVI), such as, for instance, an organo-boron oran organo-tin derivative, which in step “l2” is N-alkylated with asuitable alkylating agent of formula L-R5, to afford a compound offormula (XVI)A. Alternatively, in step “iA”, a compound of formula (II)Ais converted into an organometal derivative of formula (XVI)A. In step“i1” a compound of formula (III) is converted into an organometalderivative of formula (XVII), which in step “l3” is N-alkylated with asuitable alkylating agent of formula L-R5, to afford a compound offormula (XVI)A. Alternatively, in step “i1A”, a compound of formula(III)A is converted into an organometal derivative of formula (XVII)A.In step “h4” the reaction of a compound of formula (XVII) with ammoniaor an ammonia equivalent, affords a compound of general formula (XVI),while in step “h4A” the reaction of a compound of formula (XVII)A withammonia or an ammonia equivalent, affords a compound of general formula(XI)A.

According to steps “h5”, “h5A”, “h4” and “h4A” of scheme 3, theconversion of a compound of formula (III), (III)A, (XVII) and (XVIIA)into a compound respectively of formula (II), (IIA), (XVI) and (XVIA) isaccomplished as described under step “h” of scheme 1.

According to step “l” of scheme 3, the conversion of a compound offormula (II) in another compound of formula (IIA) can be accomplishedusing a compound of formula L-R5 wherein L is OH, in which case theMitsunobu reaction conditions can be employed, or L is a group thatoptionally upon activation, may work as a leaving group, such as ahalogen atom, a tosylate, mesylate or triflate. In the former instance,that is, when a Mitsunobu protocol is employed, the reaction can beaccomplished using a dialkyl azodicarboxylate, such as diethylazodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD) or thelike, in the presence of a trialkyl or triaryl phosphine, preferablytriphenyl phosphine in a suitable solvent such as tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane, acetonitrile. When L is a halogen atomor a group such as tosylate, mesylate or triflate or the like theconversion can be accomplished using a suitable base such as, forinstance, NaH, K₂CO₃, Cs₂CO₃, NaOH, DBU, LiHMDS and the like, in asuitable solvent such as dichloromethane, tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane, methanol, ethanol, isopropanol, acetonitrile,acetic acid, N,N-dimethylformamide, N,N-dimethylacetamide,dimethylsulfoxide and the like. Said reactions can be carried out attemperatures ranging from 0° C. to reflux and for a time ranging from 30minutes to about 48 hours. If required compounds of formula (IIA) can beseparated and purified by silica gel chromatography or preparative HPLC.

According to steps “l1”, “l2” and “l3” of scheme 3, the alkylation of acompound respectively of formula (III), (XVI) and (XVII) is accomplishedas described under step “l” of scheme 3.

According to step “i” of scheme 3, a compound of formula (II) can beconverted into a suitable organometallic derivative of formula (XVI),such as an organoboron, an organotin derivative or the like. Organoboronderivatives can be obtained for instance reacting a compound of formula(II) with a suitable boron compound, such as bis(pinacolato)diboron,pinacolborane, or the like in the presence of a suitable palladiumcatalyst such as palladium acetate (Pd(OAc)₂),1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (Pd(dppf)Cl₂.CH₂Cl₂) or Pd(CH₃CN)₂Cl₂ and of asuitable base, such as KOAc, triethylamine and the like, in solventssuch as N,N-dimethylformamide, dimethylsulfoxide, dimethoxyethane,1,4-dioxane, tetrahydrofuran, toluene or the like, at a temperatureranging from 20° C. to reflux and for a time ranging from 30 minutes toabout 24 hours. Organotin derivatives can be obtained for instance byreaction with a suitable organotin reagent such as hexamethylditin orthe like, in the presence of a suitable palladium catalyst such aspalladium tetrakis(triphenylphosphine) (Pd(PPh₃)₄) or palladium acetate(Pd(OAc)₂) optionally a suitable phosphine such as triphenylphosphine,and optionally in the presence of a suitable base, such as KOAc,triethylamine and the like, in solvents such as N,N-dimethylformamide,dimethylsulfoxide, dimethoxyethane, 1,4-dioxane, tetrahydrofuran,toluene or the like, at a temperature ranging from 20° C. to reflux andfor a time ranging from 30 minutes to about 24 hours.

According to steps “iA”, “i1” and “i1A” of scheme 3, the conversion of acompound of formula (II)A, (III) and (III)A into a compound respectivelyof formula (XVI)A, (XVII) and (XVII)A are accomplished as describedunder step “i” of scheme 3.

When preparing the compounds of formula (I) according to any variant ofthe process, which are all to be intended as within the scope of theinvention, optional functional groups within the starting materials, thereagents or the intermediates thereof, and which could give rise tounwanted side reactions, need to be properly protected according toconventional techniques.

The starting materials of the process object of the present invention,comprehensive of any possible variant, as well as any reactant thereof,are known compounds and if not commercially available per se may beprepared according to well-known methods.

Pharmacology

The biochemical activity of compounds was determined by incubation withPERK recombinant enzyme (cytoplasmic domain corresponding to residues540-1115) and eIF2alpha peptide substrate (Aminoacid sequence:LLSELSRRRIRSINK—SEQ ID Nr: 1; purchased from American Peptide Company,product #341923). This was followed by:

Method 1: Quantification of the ADP Formed from the Kinase Reaction byADP-Glo™ Kinase Assay (Promega Cat. 9102). Ultra Pure ATP was Includedinto ADP-Glo™ Kinase Assay Kit.

Compounds were 3-fold serially diluted in order to obtain from 3.333 to0.000169 microM final concentration, then incubated for 60 minutes atroom temperature in the presence of ATP, substrate and enzyme in a finalvolume of 15 microL of kinase buffer in 384-well plates (Perkin Elmercat. #6007290).

The final concentration of the different reagents is 52 microM ATP, 8 nMPERK, 300 microM substrate, 50 mM Hepes pH 7.5, 3 mM MgCl₂, 1 mM DTT, 3microM Na₃VO₄, 0.2 mg/ml BSA, 1% DMSO.

After 60 minutes, an equal volume (15 microL) of ADP-Glo™ Reagent wasadded to each well to terminate the kinase reaction and deplete theremaining ATP. After 40 minutes, 30 microL of Kinase Detection Reagentis added, which simultaneously converts ADP to ATP and allows the newlysynthesized ATP to be measured using a coupled luciferase/luciferinreaction. After further 40 minutes luminescence was read by ViewLuxInstrument (Perkin Elmer).

The data are analyzed by GraphPad Prism software which providessigmoidal fittings of the curves for IC₅₀ determination using a 4parameter logistic equation:

y=bottom+(top−bottom)/(1+10{circumflex over ( )}((log IC ₅₀ −x)*slope))

where x is the logarithm of the inhibitor concentration, y is theresponse; y starts at bottom and goes to top with a sigmoid shape.Method 2: Quantification of the Phosphorylated Product Formed from theKinase Reaction in Presence of ATP (Aldrich, Cat # A2620-9).

Serially diluted compounds were incubated for 60 minutes at roomtemperature in the presence of ATP/P³³gammaATP mix, substrate and enzymein a volume of 15 microL of kinase buffer in 384-well plates (ThermoScientific, cat #4312).

The reaction volume contains, in final concentration, 52 microM ATP, 8nM PERK and 300 microM substrate in 50 mM Hepes pH 7.5, 3 mM MgCl₂, 1 mMDTT, 3 microM Na₃VO₄, 0.2 mg/ml BSA. The final concentration of DMSO was1%.

At the end of the incubation, an amount of 60 microL of Dowex resin(Sigma, customized resin 1×8 200-400 mesh cat #13858-U) in 150 mM sodiumformate buffer pH=3.0 was added to stop the reaction and captureunreacted ATP/P³³gammaATP, separating it from the phosphorylatedsubstrate in solution. After 60 minutes of rest, a volume of 22 microLof supernatant was transferred into 384-Optiplates (Perkin-Elmer, cat#6007290). After the addition of 50 microL of Microscint 40(Perkin-Elmer, cat#6013641), the radioactivity was counted in theTopCount (Perkin Elmer).

The data per each molecule are analyzed by an internally customizedversion of the SW package “Assay Explorer”, or by GraphPad Prizmsoftware alternatively, which provides sigmoidal fittings of the curvesfor IC₅₀ determination using a 4 parameter logistic equation:

y=bottom+(top−bottom)/(1+10{circumflex over ( )}((log IC ₅₀ −x)*slope))

where x is the logarithm of the inhibitor concentration, y is theresponse; y starts at bottom and goes to top with a sigmoid shape.

The compounds were tested according to either of the above PERK enzymeassays and in at least one of the experimental run exhibited the pIC₅₀activities against PERK as shown in the following Table A:

TABLE A Cmpd # pIC₅₀ Method  1 A 1  2 AA 1  3 AA 1  4 AA 1  5 A 1  6 AA1  9 AA 1 10 C 2 11 C 2 12 A 1 13 AA 1 14 B 1 15 B 1 17 B 1 18 B 1 19 A1 20 C 1 21 C 1 22 A 1 23 B 1 24 AA 1 25 A 1 26 A 1 27 AA 1 28 A 1 29 A1 30 C 1 32 A 1 33 A 1 34 A 1 35 AA 1 36 A 1 37 A 1 38 AA 1 39 A 1 40 A1 41 A 1 44 AA 1 46 AA 1 47 A 1 48 A 1 49 B 1 50 C 1 51 A 1 52 AA 1 59 B1 60 C 1 61 A 2 62 A 2 63 A 2 64 A 1 65 B 2 66 B 2 67 C 1 71 AA 2 72 A 273 AA 2 74 B 1 75 A 1 76 B 1 77 A 2 79 A 2 81 B 1 85 A 1 86 A 1 87 AA 189 C 2 90 B 2

The results for each compound were recorded as pIC₅₀, calculated as thenegative logarithm of the IC₅₀ value (molar), and indicated by a codeaccording to the following Table B:

TABLE B Code pIC₅₀ value AA 7.8 ≤ pIC₅₀ A 7.3 ≤ pIC₅₀ < 7.8 B 6.8 ≤pIC₅₀ < 7.3 C pIC₅₀ < 6.8

From all of the above, the novel compounds of formula (I) of theinvention appear to be particularly advantageous in the therapy ofdiseases caused by deregulated protein kinase activity such as cancer.

The compounds of the present invention can be administered either assingle agents or, alternatively, in combination with known anticancertreatments such as radiation therapy or chemotherapy regimen incombination with, for example, antihormonal agents such asantiestrogens, antiandrogens and aromatase inhibitors, topoisomerase Iinhibitors, topoisomerase II inhibitors, agents that targetmicrotubules, platin-based agents, alkylating agents, DNA damaging orintercalating agents, antineoplastic antimetabolites, other kinaseinhibitors, other anti-angiogenic agents, inhibitors of kinesins,therapeutic monoclonal antibodies, inhibitors of mTOR, histonedeacetylase inhibitors, farnesyl transferase inhibitors, and inhibitorsof hypoxic response.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described below andthe other pharmaceutically active agent within the approved dosagerange.

Compounds of formula (I) may be used sequentially with known anticanceragents when a combination formulation is inappropriate.

The compounds of formula (I) of the present invention, suitable foradministration to a mammal, e.g., to humans, can be administered by theusual routes and the dosage level depends upon the age, weight, andconditions of the patient and administration route.

For example, a suitable dosage adopted for oral administration of acompound of formula (I) may range from about 10 g to about 1 g per dose,from 1 to 5 times daily. The compounds of the invention can beadministered in a variety of dosage forms, e.g., orally, in the formtablets, capsules, sugar or film coated tablets, liquid solutions orsuspensions; rectally in the form suppositories; parenterally, e.g.,intramuscularly, or through intravenous and/or intrathecal and/orintraspinal injection or infusion.

The present invention also includes pharmaceutical compositionscomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof in association with a pharmaceutically acceptableexcipient, which may be a carrier or a diluent.

The pharmaceutical compositions containing the compounds of theinvention are usually prepared following conventional methods and areadministered in a suitable pharmaceutical form.

For example, the solid oral forms may contain, together with the activecompound, diluents, e.g., lactose, dextrose saccharose, sucrose,cellulose, corn starch or potato starch; lubricants, e.g., silica, talc,stearic acid, magnesium or calcium stearate, and/or polyethyleneglycols; binding agents, e.g., starches, arabic gum, gelatinemethylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone;disintegrating agents, e.g., starch, alginic acid, alginates or sodiumstarch glycolate; effervescing mixtures; dyestuffs; sweeteners; wettingagents such as lecithin, polysorbates, laurylsulphates; and, in general,non-toxic and pharmacologically inactive substances used inpharmaceutical formulations. These pharmaceutical preparations may bemanufactured in known manner, for example, by means of mixing,granulating, tabletting, sugar-coating, or film-coating processes.

The liquid dispersions for oral administration may be, e.g., syrups,emulsions and suspensions.

As an example the syrups may contain, as a carrier, saccharose orsaccharose with glycerine and/or mannitol and sorbitol.

The suspensions and the emulsions may contain, as examples of carriers,natural gum, agar, sodium alginate, pectin, methylcellulose,carboxymethylcellulose, or polyvinyl alcohol.

The suspension or solutions for intramuscular injections may contain,together with the active compound, a pharmaceutically acceptablecarrier, e.g., sterile water, olive oil, ethyl oleate, glycols, e.g.,propylene glycol and, if desired, a suitable amount of lidocainehydrochloride.

The solutions for intravenous injections or infusions may contain, as acarrier, sterile water or preferably they may be in the form of sterile,aqueous, isotonic, saline solutions or they may contain propylene glycolas a carrier.

The suppositories may contain, together with the active compound, apharmaceutically acceptable carrier, e.g., cocoa butter, polyethyleneglycol, a polyoxyethylene sorbitan fatty acid ester surfactant orlecithin.

EXPERIMENTAL SECTION

For a reference to any specific compound of formula (I) of theinvention, optionally in the form of a pharmaceutically acceptable salt,see the experimental section and claims. Referring to the examples thatfollow, compounds of the present invention were synthesized using themethods described herein, or other methods, which are well known in theart.

The short forms and abbreviations used herein have the followingmeaning:

g (grams) mL (milliliters) μM (micromolar) h (hours) mm (millimetres) M(molar) mol (moles) r.t. (room temperature) TFA (trifluoroacetic acid)DIPEA (N,N-diisopropyl-N-ethylamine) THF (tetrahydrofuran) Hex (hexane)DMSO (dimethylsulfoxide) Ac (acetyl) TBDMS (dimethyl-tert-butylsilyl)BOC (tert-butyloxycarbonyl) NaH (sodium hydride, 60% in mineral oil)TBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate) RP-HPLC (reverse phase high performance liquidchromatography) mg (milligrams) mM (millimolar) mmol (millimoles) MHz(Mega-Hertz) Hz (Hertz) min (minutes) TLC (thin layer chromatography)TEA (triethylamine) DMF (N,N-dimethyl formamide) DCM (dichloromethane)AcOET (ethyl acetate) MeOH (Methanol) TIPS (triisopropylsilyl) bs (broadsinglet) ESI (electrospray ionization) Ac₂O (acetic anhydride)

With the aim to better illustrate the present invention, without posingany limitation to it, the following examples are now given.

As used herein the symbols and conventions used in the processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry.

Unless otherwise noted, all materials were obtained from commercialsuppliers, of the best grade and used without further purification.Anhydrous solvent such as DMF, THF, CH₂Cl₂ and toluene were obtainedfrom the Aldrich Chemical Company. All reactions involving air- ormoisture-sensitive compounds were performed under nitrogen or argonatmosphere.

General Purification and Analytical Methods

Flash Chromatography was performed on silica gel (Merck grade 9395,60A).

Electrospray (ESI) mass spectra were obtained on a Thermo Finnigan LCQDeca XP ion trap. HPLC-UV-MS analyses, used to assess compound purity,were carried out combining the ion trap MS instrument with HPLC systemSurveyor (Thermo Finnigan) equipped with an autosampler and a diodearray detector (UV detection 215-400 nm). Instrument control, dataacquisition and processing were performed by using Xcalibur 1.4 SR1software (Thermo Finnigan). HPLC chromatography was run at roomtemperature, and 1 ml/min flow rate, using a Phenomenex Gemini NX C18column (4.6×50 mm; 3 μm). Mobile phase A was ammonium acetate 5 mMbuffer (pH 5.5 with acetic acid):acetonitrile 95:5, and mobile phase Bwas ammonium acetate 5 mM buffer (pH 5.5 with acetic acid):acetonitrile5:95; the gradient was from 0 to 100% B in 7 minutes then hold 100% Bfor 2 minutes before requilibration.

Exact mass data ESI(+) were obtained on a Waters Q-Tof Ultima directlyconnected with micro HPLC 1100 Agilent as previously described [M.Colombo, F. Riccardi-Sirtori, V. Rizzo, Rapid Commun. Mass Sectrom.2004, 18, 511-517].

Retention times (HPLC r.t.) are given in minutes at 220 nm or at 254 nm.Mass are given as m/z ratio.

When necessary, compounds were purified by preparative HPLC on a WatersSymmetry C18 (19×50 mm, 5 um) column or on a Waters X Terra RP 18(30×150 mm, 5 μm) column using a Waters preparative HPLC 600 equippedwith a 996 Waters PDA detector and a Micromass mod. ZMD singlequadrupole mass spectrometer, electron spray ionization, positive mode.Mobile phase A was water-0.01% trifluoroacetic acid, and mobile phase Bwas acetonitrile. Gradient from 10 to 90% B in 8 min, hold 90% B 2 min.Flow rate 20 mL/min. In alternative, mobile phase A was water-0.1% NH₃,and mobile phase B was acetonitrile. Gradient from 10 to 100% B in 8min, hold 100% B 2 min. Flow rate 20 mL/min.

1H-NMR spectrometry was performed on a Mercury VX 400 operating at400.45 MHz equipped with a 5 mm double resonance probe [1H (15N-31P)ID_PFG Varian].

Preparation 1 5-Iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine,Compound of Formula (II)A Scheme 34-Chloro-5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine, Compound ofFormula (III)A Scheme 3, Step I1

To 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (2.38 g, 8.5 mmol) inN,N-dimethylformamide (DMF) (80 mL) at 0° C. was added 60% NaH (0.59 g,14.7 mmol) portionwise. After H₂ bubbling stopped, iodomethane (0.66 mL,10.6 mmol) was added and the reaction mixture was allowed to warm atroom temperature. After 3 hours, the reaction mixture was poured slowlyonto water and crushed ice (about 400 mL; Caution: H₂ evolution due toquenching excess NaH). The resulting white solid was filtered and washedwith water and dried under vacuum to afford4-chloro-5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (2.38 g).

HPLC (254 nm): Rt: 8.62 min.

HRMS (ESI) calcd for C₇H₅ClIN₃ [M+H]⁺ 293.929, found 293.9296.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 3.83 (s, 3H) 7.98 (s, 1H) 8.65 (s,1H).

Analogously the following compounds were obtained:

4-Chloro-5-iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine, Compound ofFormula (III)A

HPLC (254 nm): Rt: 11.17 min.

HRMS (ESI) calcd for C₉H₉ClIN₃ [M+H]⁺ 321.9603, found 321.9605.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 1.47 (d, J=6.71 Hz, 6H) 4.92-5.15(m, 1H) 8.16 (s, 1H) 8.63 (s, 1H).

4-Chloro-7-ethyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine, Compound of Formula(III)A

HPLC (254 nm): Rt: 6.16 min.

HRMS (ESI) calcd for C₈H₇ClIN₃ [M+H]⁺ 307.9446, found 307.9455.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 1.37 (t, J=7.24 Hz, 3H) 4.29 (q,J=7.22 Hz, 2H) 8.07 (s, 1H) 8.64 (s, 1H).

5-Iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine, Compound ofFormula (II)A Scheme 3, Step h5A

A suspension of 4-chloro-5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine(1.16 g, 3.96 mmol) in ammonium hydroxide (10 mL, 75.43 mmol) anddioxane (5 mL) was stirred for 1 day at 125° C. in a sealed vessel. Thereaction was allowed to cool to room temperature and poured in water andice and filtered. The collected solid was washed with water to afford5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (0.93 g) as whitesolid.

HPLC (254 nm): Rt: 4.06 min.

HRMS (ESI) calcd for C₇H₇IN₄ [M+H]⁺ 274.9788, found 274.9796.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 3.67 (s, 3H) 6.59 (br. s., 2H) 7.42(s, 1H) 8.10 (s, 1H).

Analogously the following compound was obtained:

5-Iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine, Compound ofFormula (II)A

HPLC (254 nm): Rt: 4.99 min.

HRMS (ESI) calcd for C₉H₁₁N₄[M+H]⁺ 303.0101, found 303.0105.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 1.40 (d, J=6.71 Hz, 6H) 4.89 (quin,J=6.74 Hz, 1H) 6.55 (br. s., 2H) 7.57 (s, 1H) 8.08 (s, 1H).

7-Ethyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine, Compound of Formula(II)A

HPLC (254 nm): Rt: 3.27 min.

HRMS (ESI) calcd for C₈H₉IN₄ [M+H]⁺ 288.9945, found 288.9957.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 1.31 (t, J=7.26 Hz, 3H) 4.13 (d,J=7.20 Hz, 2H) 6.38-6.72 (m, 2H) 7.47-7.50 (m, 1H) 8.09 (s, 1H).

Preparation 2 3-Iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine,Compound of Formula (II)A Scheme 3, Step I

To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (550 mg,2.044 mmol) in DMF (20 mL) at 0° C. were added Cs₂CO₃ (770 mg, 2.362mmol) and iodomethane (0.16 mL, 2.57 mmol). The reaction was allowed towarm at room temperature and stirred overnight. The reaction mixture waspoured onto water and extracted with DCM. The organic phase was washedwith brine, dried over Na₂SO₄ and evaporated. The crude was purified bysilica gel chromatography which was eluted with DCM:MeOH=95:5 and theresulting solid triturated with Et₂O to give3-Iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (170 mg) as whitesolid.

HPLC (254 nm): Rt: 3.55 min.

HRMS (ESI) calcd for C6H6IN5 [M+H]⁺ 275.9741, found 275.9743.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 3.88 (s, 3H) 7.49 (s, 2H) 8.21 (s,1H).

Preparation 35-Iodo-7-(1-methyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine,Compound of Formula (II)A Scheme 34-(4-Chloro-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-piperidine-1-carboxylicAcid tert-butyl Ester, Compound of Formula (III)A Scheme 3, Step I1

To a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (518 mg,1.857 mmol), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester(1.14 g, 5.671 mmol) and triphenylphosphine (984 mg, 3.775 mmol) in THF(10 mL) were added dropwise via syringe DEAD (0.6 mL, 3.669 mmol) andstirred for 3 h at room temperature. The reaction was concentrated,diluted with AcOEt and washed with NaOH 1.0N. The organic layer was thenwashed with brine, dried over Na₂SO₄ and evaporated. The crude waspurified by silica gel chromatography which was eluted withHexane:AcOEt=7:3 to afford4-(4-chloro-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-piperidine-1-carboxylicacid tert-butyl ester (730 mg) as white solid.

HPLC (254 nm): Rt: 7.38 min.

HRMS (ESI) calcd for C₁₆H₂0N₄O₂ICl [M+H]⁺ 463.0393, found 463.04.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 1.43 (s, 9H) 1.82-1.92 (m, 2H)1.92-2.04 (m, 2H) 2.94 (br. s., 2H) 4.11 (m, J=11.60 Hz, 2H) 4.72-4.95(m, 1H) 8.19 (s, 1H) 8.64 (s, 1H).

Analogously the following compound was obtained:

4-Chloro-5-iodo-7-(tetrahydro-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine,Compound of Formula (III)A

HPLC (254 nm): Rt: 5.97 min.

HRMS (ESI) calcd for C₁₁H₁₁N₃OICl [M+H]⁺ 363.9708, found 363.9724.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 1.87 (dd, J=12.39, 2.26 Hz, 2H)2.06-2.24 (m, 2H) 3.52 (td, J=11.84, 1.59 Hz, 2H) 3.99 (dd, J=11.47,4.39 Hz, 2H) 4.82-5.00 (m, 1H) 8.18 (s, 1H) 8.64 (s, 1H).

4-Chloro-5-iodo-7-piperidin-4-yl-7H-pyrrolo[2,3-d]pyrimidine, Compoundof Formula (III)A Scheme 3

To4-(4-chloro-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-piperidine-1-carboxylicacid tert-butyl ester (240 mg, 0.519 mmol) in dioxane (8 mL) was addedHCl in dioxane 4M (4 ml, 16 mmol) and the reaction stirred at 45° C.overnight. The reaction solvent was evaporated and the resulting whitesolid was diluted with DCM and NaOH 1.0N. The water layer was extractedwith DCM and the combined organic phase was washed with brine, driedover Na₂SO₄ and evaporated to furnished4-chloro-5-iodo-7-piperidin-4-yl-7H-pyrrolo[2,3-d]pyrimidine (157 mg) aswhite solid.

HPLC (254 nm): Rt: 4.29 min.

HRMS (ESI) calcd for C₁₁H₁₂N₄ICl [M+H]⁺ 362.9868, found 362.9874.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 1.90-2.00 (m, 2H) 2.00-2.16 (m, 2H)2.79-2.94 (m, 2H) 3.12-3.28 (m, 2H) 4.74-4.87 (m, 1H) 8.08 (s, 1H) 8.65(s, 1H).

Analogously the following compound was obtained:

5-Iodo-7-piperidin-4-yl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine, Compoundof Formula (II)A

HPLC (254 nm): Rt: 3.17 min.

HRMS (ESI) calcd for C₁₁H₁₄IN₅ [M+H]⁺ 344.0367, found 344.0369.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 1.60-1.90 (m, 4H) 2.55-2.62 (m, 2H)3.03 (d, J=12.51 Hz, 2H) 4.47-4.62 (m, 1H) 5.71-7.16 (m, 2H) 7.52 (s,1H) 8.07 (s, 1H).

4-Chloro-5-iodo-7-(1-methyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine,Compound of Formula (III)A Scheme 3

To 4-chloro-5-iodo-7-piperidin-4-yl-7H-pyrrolo[2,3-d]pyrimidine (518 mg,1.430 mmol) in DCM (15 mL) was added AcOH (90 microL, 1.575 mmol),formaldehyde solution 37 wt. % in water (550 microL, 7.346 mmol) andstirred at room temperature. After 15 min was added NaBH(OAc)₃ (1.62 g,7.412 mmol) portionwise and the reaction was let to stir at roomtemperature overnight. The mixture was diluted with DCM and washed withNaOH 2.0N. The organic layer was washed with brine, dried over Na₂SO₄and evaporated to afford4-chloro-5-iodo-7-(1-methyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine(491 mg) as white solid.

HPLC (254 nm): Rt: 4.37 min.

HRMS (ESI) calcd for C₁₂H₁₄N₄ICl [M+H]⁺ 377.0025, found 377.0042.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 1.88 (m, J=8.91 Hz, 2H) 2.03-2.18(m, 4H) 2.23 (s, 3H) 2.91 (m, J=8.67 Hz, 2H) 4.62 (m, J=11.63, 11.63,4.33 Hz, 1H) 8.15 (s, 1H) 8.63 (s, 1H).

Analogously the following compounds were obtained:

4-Chloro-5-iodo-7-(1-isopropyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine,Compound of Formula (III)A

HPLC (254 nm): Rt: 4.63 min.

HRMS (ESI) calcd for C₁₄H₁₈N₄ICl [M+H]⁺ 405.0338, found 405.0346.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 1.00 (d, J=6.56 Hz, 6H) 1.84-1.94(m, 2H) 1.98-2.13 (m, 2H) 2.24-2.35 (m, 2H) 2.76 (br. s., 1H) 2.92 (d,J=10.68 Hz, 2H) 4.61 (t, J=12.35 Hz, 1H) 8.16 (s, 1H) 8.63 (s, 1H).

4-Chloro-7-(1-cyclopropyl-piperidin-4-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine,Compound of Formula (III)A

HPLC (254 nm): Rt: 6.35 min.

HRMS (ESI) calcd for C₁₄H₁₆N₄ICl [M+H]⁺ 403.0181, found 403.0183.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 0.28-0.37 (m, 2H) 0.40-0.48 (m, 2H)1.63-1.73 (m, 1H) 1.81-1.93 (m, 2H) 2.05 (s, 3H) 2.31-2.42 (m, 2H)3.02-3.12 (m, 1H) 4.61-4.74 (m, 1H) 8.14 (s, 1H) 8.63 (s, 1H).

5-Iodo-7-(1-methyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine,Compound of Formula (II)A Scheme 3, Step h5A

To a 5 mL microwave vial charged with dioxane (4 mL) was added4-chloro-5-iodo-7-(1-methyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine(469 mg, 1.247 mmol), ammonium hydroxide (10 mL, 76.46 mmol) and sealed.The reaction vessel was heated under microwave irradiation for 180 minat 130° C. The mixture was diluted with water and extracted with DCM.The combined organic phase was washed with brine, dried over Na₂SO₄ andevaporated. The solid obtained was triturated with Et₂O to afford5-Iodo-7-(1-methyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine(374 mg) as white solid.

HPLC (254 nm): Rt: 3.22 min.

HRMS (ESI) calcd for C₁₂H₁₆N₅I [M+H]⁺ 358.0523, found 358.0535.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 1.74-1.87 (m, 2H) 1.94-2.12 (m, 4H)2.23 (s, 3H) 2.89 (m, J=8.06 Hz, 2H) 4.31-4.60 (m, 1H) 6.57 (br. s., 2H)7.56 (s, 1H) 8.08 (s, 1H).

Analogously the following compounds were obtained:

5-Iodo-7-(1-isopropyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine,Compound of Formula (II)A

HPLC (254 nm): Rt: 3.50 min.

HRMS (ESI) calcd for C₁₄H₂0N₅I [M+H]⁺ 386.0836, found 386.0845.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 0.99 (d, J=6.56 Hz, 6H) 1.82 (dt,J=11.78, 1.81 Hz, 2H) 1.96 (qd, J=12.20, 3.97 Hz, 2H) 2.26 (t, J=11.21Hz, 2H) 2.74 (spt, J=6.60 Hz, 1H) 2.89 (d, J=11.44 Hz, 2H) 4.45 (tt,J=11.93, 3.85 Hz, 1H) 6.58 (br. s., 2H) 7.57 (s, 1H) 8.08 (s, 1H).

7-(1-Cyclopropyl-piperidin-4-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine,Compound of Formula (II)A

HPLC (254 nm): Rt: 4.04 min.

HRMS (ESI) calcd for C₁₄H₁₈N₅I [M+H]⁺ 384.068, found 384.0689.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 0.27-0.34 (m, 2H) 0.41-0.48 (m, 2H)1.67 (tt, J=6.58, 3.49 Hz, 1H) 1.79 (d, J=11.59 Hz, 2H) 1.95 (qd,J=12.23, 3.43 Hz, 2H) 2.32 (t, J=11.29 Hz, 2H) 3.04 (d, J=11.90 Hz, 2H)4.51 (tt, J=11.95, 3.98 Hz, 1H) 6.59 (br. s., 2H) 7.55 (s, 1H) 8.08 (s,1H).

5-Iodo-7-(tetrahydro-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine,Compound of Formula (II)A

HPLC (254 nm): Rt: 4.42 min.

HRMS (ESI) calcd for C₁₁H₁₃IN₄O [M+H]⁺ 345.0207, found 345.0213.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 1.80 (m, J=12.27, 2.38 Hz, 2H)1.98-2.12 (m, 2H) 3.48 (td, J=11.93, 1.77 Hz, 2H) 3.97 (dd, J=11.35,4.27 Hz, 2H) 4.63-4.86 (m, 1H) 6.59 (br. s., 2H) 7.60 (s, 1H) 8.09 (s,1H).

4-(4-Amino-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-piperidine-1-carboxylicAcid tert-butyl Ester, Compound of Formula (II)A

To a 5 mL microwave vial charged with dioxane (1 mL) was added4-(4-chloro-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-piperidine-1-carboxylicacid tert-butyl ester (115 mg, 0.249 mmol), ammonium hydroxide (2 mL,16.6 mmol) and sealed. The reaction vessel was heated under microwaveirradiation for 120 min at 100° C. The mixture was diluted with waterand extracted with DCM. The combined organic phase was washed withbrine, dried over Na₂SO₄ and evaporated. The crude was purified bysilica gel chromatography which was eluted with DCM:MeOH=90:10 to afford4-(4-amino-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-piperidine-1-carboxylicacid tert-butyl ester (80 mg) as white solid.

HPLC (254 nm): Rt: 5.98 min.

HRMS (ESI) calcd for C₁₆H₂₂N₅O₂I [M+H]⁺ 444.0891, found 444.088.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 1.42 (s, 9H) 1.69-1.94 (m, 4H)2.75-3.02 (m, 2H) 4.04-4.23 (m, 2H) 4.59-4.79 (m, 1H) 6.59 (br. s., 2H)7.61 (s, 1H) 8.08 (s, 1H).

Preparation 44-(4-Amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylicAcid tert-butyl Ester, Compound of Formula (II)A Scheme 3, Step I

To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (300 mg,1.115 mmol), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester(680 mg, 3.383 mmol) and triphenylphosphine (593 mg, 2.263 mmol) in THF(10 mL) was added dropwise via syringe DEAD (0.37 mL, 2.262 mmol) andstirred for 3 h at room temperature. The reaction was concentrated,diluted with AcOEt and washed with NaOH 1.0N. The organic layer waswashed with brine, dried over Na₂SO₄ and evaporated. The crude waspurified by silica gel chromatography which was eluted withHexane:AcOEt=1:1 to afford4-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylicacid tert-butyl ester (300 mg) as white solid.

HPLC (254 nm): Rt: 5.72 min.

HRMS (ESI) calcd for C₁₅H₂₁N₆O₂I [M+H]⁺ 445.0844, found 445.0839.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 1.43 (s, 9H) 1.79-1.93 (m, 4H) 2.95(br. s., 2H) 3.91-4.20 (m, 2H) 4.81 (tt, J=10.51, 5.23 Hz, 1H) 5.91-7.38(m, 2H) 8.19 (s, 1H).

Preparation 5 3-Bromo-thieno[3,2-c]pyridin-4-ylamine, Compound ofFormula (II) Scheme 3, Step h5

3-Bromo-4-chloro-thieno[3,2-c]pyridine (300 mg, 1.21 mmol) was dissolvedin NMP (3 mL) and placed in a 20-mL microwave vial. A saturated solutionof NH₄Cl (5 mL) was added to the vial and the mixture was microwaveheated at 150° C. for a total time of 3 h. The mixture was then dilutedwith water and extracted with ethyl acetate. The aqueous solution wasthen basified with NaOH and extracted with AcOEt. The latter solutionwas dried with Na₂SO₄ and evaporated to dryness. The residue waspurified by flash column chromatography over silica gel eluting with DCMto yield 3-bromo-thieno[3,2-c]pyridin-4-ylamine (84 mg).

HPLC (254 nm): Rt: 4.38 min.

HRMS (ESI) calcd for C₇H₅BrN₂S [M+H]⁺ 228.9430, found 228.9441.

1H NMR (500 MHz, DMSO-d6) delta ppm: 6.49 (s, 2H) 7.27 (d, J=5.64 Hz,1H) 7.78 (s, 1H) 7.83 (d, J=5.64 Hz, 1H).

Analogously the following compound was obtained:

3-Bromo-furo[3,2-c]pyridin-4-ylamine, Compound of Formula (II)

HPLC (254 nm): Rt: 3.91 min.

HRMS (ESI) calcd for C₇H₅BrN₂S [M+H]⁺ 212.9658, found 212.9659.

1H NMR (500 MHz, DMSO-d6) delta ppm: 1H NMR (500 MHz, DMSO-d6) 6.19 (br.s., 2H) 6.92 (d, J=5.95 Hz, 1H) 7.85 (d, J=5.95 Hz, 1H) 8.12 (s, 1H).

Preparation 62-Fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine,Compound of Formula (VI) Scheme 1

A mixture of 3-bromo-2-fluoro-phenylamine (6.52 g, 33.63 mmol),bis(pinacolato)diboron (10.45 g, 41.14 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (1.12 g, 1.37 mmol) and potassium acetate(10.1 g, 103.06 mmol) in dry DMF (65 mL) was heated at 100° C. under anatmosphere of nitrogen for 7 hours. The reaction was allowed to cool toroom temperature, diluted with AcOEt and filtered through celite. Theorganic was washed with water, brine, dried over Na₂SO₄ and evaporated.The crude was purified by silica gel chromatography which was elutedwith hexane:AcOEt=8:2 to afford2-fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine(6.90 g) as white solid.

HPLC (254 nm): Rt: 5.94 min.

HRMS (ESI) calcd for C₁₂H₁₇BNO₂F [M+H]⁺ 237.1446, found 237.1453.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 1.28 (s, 12H) 4.99 (s, 2H)6.67-6.78 (m, 1H) 6.80-6.92 (m, 2H).

Analogously the following compounds were obtained:

2-Chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine,Compound of Formula (VI)

HRMS (ESI) calcd for C₁₂H₁₇BNO₂Cl [M+H]⁺ 253.115, found 253.114.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 1.28 (s, 12H) 5.27 (s, 2H) 6.77(dd, J=7.09, 1.60 Hz, 1H) 6.86 (dd, J=7.93, 1.68 Hz, 1H) 6.95-7.03 (m,1H).

2-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine,Compound of Formula (VI)

HPLC (254 nm): Rt: 6.34 min.

HRMS (ESI) calcd for C₁₃H₂₀BNO₂ [M+H]⁺ 233.1696, found 233.1698.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 1.28 (s, 12H) 2.20 (s, 3H) 4.70 (s,2H) 6.67-6.73 (m, 1H) 6.83-6.90 (m, 2H).

2-Amino-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile,Compound of Formula (VI)

HRMS (ESI) calcd for C₁₃H₁₇BN₂O₂[M+Na]⁺ 266.1311, found 266.1307.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 1.29 (s, 12H) 5.93 (s, 2H) 6.90(ddd, J=9.72, 7.82, 1.07 Hz, 2H) 7.24-7.33 (m, 1H).

Preparation 7[2-Fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-carbamicAcid tert-butyl Ester, Compound of Formula (IV) Scheme 1(3-Bromo-2-fluoro-phenyl)-carbamic Acid tert-butyl Ester

To a suspension of 3-bromo-2-fluoro-phenylamine (5.48 g, 28.84 mmol) inNaOH 2N (100 mL, 200 mmol) was added di-tert-butyl dicarbonate (10.07 g,46.19 mmol) and the mixture was kept under mechanic stirring and heatedat reflux. After 24 hours the reaction was cool down at roomtemperature, diluted with DCM (100 mL) and the organic was separated.The aqueous layer was extracted with DCM and the combined organic phasewas washed with brine, dried over Na₂SO₄ and evaporated. The crude waspurified by silica gel chromatography (gradient: hexane:AcOEt=100:0 to70:30) to recover unreacted starting material (1.10 g) and afford thetitle compound (6.43 g) as white solid.

HPLC (254 nm): Rt: 7.37 min.

HRMS (ESI) calcd for C₁₃H₂0BNO₂ [M+Na]⁺ 312.0006, found 312.0004.

¹H NMR (600 MHz, DMSO-d6) delta ppm: 1.46 (s, 9H) 7.09 (t, J=7.69 Hz,1H) 7.29-7.44 (m, 1H) 7.60 (t, J=7.51 Hz, 1H) 9.16 (s, 1H).

[2-Fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-carbamicAcid tert-butyl Ester, Compound of Formula (IV) Scheme 1

In a sealed tube, to (3-bromo-2-fluoro-phenyl)-carbamic acid tert-butylester (4.08 g, 14.07 mmol), bis(pinacolato)diboron (5.55 g, 21.85 mmol)and potassium acetate (4.35 g, 44.38 mmol) was added dioxane (100 mL)and the mixture was degassed with N₂. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (559mg, 0.684 mmol) was added and the reaction was stirred at 100° C.overnight. The mixture was cooled down at room temperature, diluted withAcOEt and passed through celite. The combined organic layer wasevaporated and the crude was purified by silica gel chromatography(gradient hexane:AcOEt=100:0 to 70:30) to furnish the title compound(4.6 g) as a solid.

HRMS (ESI) calcd for C₁₇H₂₅BFNO₄ [M+Na]⁺ 359.1789, found 359.1791.

¹H NMR (600 MHz, DMSO-d6) delta ppm: 1.29 (s, 12H) 1.46 (s, 9H) 7.12 (t,J=7.60 Hz, 1H) 7.33 (ddd, J=7.19, 5.27, 1.65 Hz, 1H) 7.70 (t, J=7.51 Hz,1H) 8.86 (s, 1H).

Preparation 83-Chloro-N-[2-fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-4-methoxy-N-methoxymethyl-benzenesulfonamide,Compound of Formula (IX) Scheme 1N-(3-Bromo-2-fluoro-phenyl)-3-chloro-4-methoxy-benzenesulfonamide,Compound of Formula (XX) Scheme 3

To a solution of 3-bromo-2-fluoro-phenylamine (1.10 g, 5.67 mmol) in DCM(50 mL) was added pyridine (0.68 mL, 8.51 mmol),3-chloro-4-methoxy-benzenesulfonyl chloride (1.37 g, 5.70 mmol) andstirred at room temperature overnight. The reaction mixture was dilutedwith DCM, washed with saturated aqueous NaHCO₃, saturated aqueous NH₄Cl,brine and dried over Na₂SO₄. The organic solvent was removed underreduce pressure and the crude triturated with Et₂O to give the titlecompound (1.63 g) as a white solid.

HPLC (254 nm): Rt: 5.74 min.

HRMS (ESI) calcd for C₁₃H₁₀BrClFNO₃S [M+Na]⁺ 415.9129, found 415.9135.

¹H NMR (600 MHz, DMSO-d6) delta ppm: 3.93 (s, 3H) 7.10 (td, J=8.10, 1.19Hz, 1H) 7.22-7.25 (m, 1H) 7.31 (d, J=8.79 Hz, 1H) 7.47-7.52 (m, 1H) 7.66(dd, J=8.70, 2.29 Hz, 1H) 7.74 (d, J=2.38 Hz, 1H) 10.37 (s, 1H).

N-(3-Bromo-2-fluoro-phenyl)-3-chloro-4-methoxy-N-methoxymethyl-benzenesulfonamide,Compound of Formula (XXI) Scheme 3

To a solution ofN-(3-bromo-2-fluoro-phenyl)-3-chloro-4-methoxy-benzenesulfonamide (505mg, 1.282 mmol) in DCM (15 mL) was added DIPEA (0.35 mL, 2.048 mmol) andchloro-methoxy-methane (0.16 mL, 2.055 mmol) and stirred overnight atroom temperature. The reaction was diluted with DCM, washed withsaturated NH₄Cl, brine and dried over Na₂SO₄. The organic solvent wasremoved under reduce pressure to give the title compound (480 mg) as asolid.

HPLC (254 nm): Rt: 6.99 min.

HRMS (ESI) calcd for C₁₅H₁₄BrClFNO₄S [M+Na]⁺ 459.9391, found 459.9391.

¹H NMR (600 MHz, DMSO-d6) delta ppm: 3.30 (s, 3H) 3.97 (s, 3H) 4.99 (s,2H) 7.07-7.23 (m, 2H) 7.34 (d, J=8.79 Hz, 1H) 7.64 (dd, J=8.79, 2.38 Hz,1H) 7.72 (d, J=2.38 Hz, 1H) 7.74-7.79 (m, 1H).

Analogously the following compound was obtained:

N-(3-Bromo-2-cyano-phenyl)-5-chloro-2-fluoro-4-methoxy-N-methoxymethyl-benzenesulfonamide,Compound of Formula (XXI)

HPLC (254 nm): Rt: 6.74 min.

HRMS (ESI) calcd for C₁₆H₁₃BrClFN₂O₄S [M+Na]⁺ 484.9344, found 484.9331.

1H NMR (500 MHz, DMSO-d6) delta ppm: 3.40 (s, 3H) 3.98 (s, 3H) 5.09 (s,2H) 7.37 (d, J=8.08 Hz, 1H) 7.43 (d, J=12.35 Hz, 1H) 7.64 (d, J=7.47 Hz,1H) 7.67 (t, J=8.16 Hz, 1H) 7.96 (dd, J=8.24, 0.92 Hz, 1H).

3-Chloro-N-[2-fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-4-methoxy-N-methoxymethyl-benzenesulfonamide,Compound of Formula (IX) Scheme 1

In a Schlenk tube, toN-(3-bromo-2-fluoro-phenyl)-3-chloro-4-methoxy-N-methoxymethyl-benzenesulfonamide(479 mg, 1.093 mmol), bis(pinacolato)diboron (345 mg, 1.358 mmol) andpotassium acetate (295 mg, 3.010 mmol) was added dioxane (12 mL) and themixture was degassed with N₂.[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (47 mg, 0.057 mmol) was added and thereaction stirred at 100° C. overnight. The mixture was cool down at roomtemperature, diluted with AcOEt and passed through celite. The combinedorganic layer was evaporated and the crude was purified by silica gelchromatography (gradient hexane:AcOEt=80:20 to 60:40) to furnish thetitle compound (400 mg) as a solid.

MS (ESI) for C₂₁H₂₆BClFNO₆S (MW:485.77): [M+H]⁺ found 486

Preparation 93-Chloro-N-[2-fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-4-methoxy-benzenesulfonamide,Compound of Formula (VIII) Scheme 1

To a solution of2-fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine(163 mg, 0.685 mmol) in DCM (10 mL) were added pyridine (0.28 mL, 3.484mmol), 3-chloro-4-methoxy-benzenesulfonyl chloride (197 mg, 0.820 mmol)and stirred at room temperature for 2 h. The reaction was diluted withDCM and washed with saturated NaHCO₃, brine and dried over Na₂SO₄. Theorganic solvent was evaporated under vacuum and the residue wastriturated with hexane to give the title compound (250 mg) as a solid.

HRMS (ESI) calcd for C₁₉H₂₂BClFNO₅S [M+Na]⁺ 463.0913, found 463.0897.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 1.20-1.31 (m, 12H) 3.91 (s, 3H)7.13 (t, J=7.63 Hz, 1H) 7.29 (d, J=8.85 Hz, 1H) 7.35-7.42 (m, 1H) 7.65(dd, J=8.85, 2.29 Hz, 1H) 7.69 (d, J=2.14 Hz, 1H) 7.93 (t, J=7.63 Hz,1H) 10.09-10.21 (m, 1H).

Analogously the following compounds were obtained:

5-Chloro-2-fluoro-N-[2-fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-4-methoxy-benzenesulfonamide,Compound of Formula (VIII)

¹H NMR (401 MHz, DMSO-d6) delta ppm: 1.27 (s, 12H) 3.94 (s, 3H) 7.14 (t,J=7.60 Hz, 1H) 7.33-7.46 (m, 3H) 7.63 (d, J=7.32 Hz, 1H) 10.38 (s, 1H).

3-Chloro-N-[2-chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-4-methoxy-benzenesulfonamide,Compound of Formula (VIII)

HRMS (ESI) calcd for C₁₉H₂₂BCl₂NO₅S [M+Na]⁺ 479.0617, found 479.0607.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 1.28 (s, 12H) 3.93 (s, 3H)7.24-7.34 (m, 3H) 7.42 (dd, J=6.94, 2.06 Hz, 1H) 7.65 (dd, J=8.69, 2.29Hz, 1H) 7.74 (d, J=2.44 Hz, 1H) 9.97 (s, 1H).

5-Chloro-N-[2-chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-fluoro-4-methoxy-benzenesulfonamide,Compound of Formula (VIII)

¹H NMR (500 MHz, DMSO-d6) delta ppm: 1.28 (s, 12H) 3.95 (s, 3H)7.27-7.33 (m, 1H) 7.34-7.39 (m, 2H) 7.46 (dd, J=7.32, 1.68 Hz, 1H) 7.61(d, J=7.32 Hz, 1H) 10.29 (s, 1H).

3,4-Dichloro-N-[2-fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzenesulfonamide,Compound of Formula (VIII)

¹H NMR (500 MHz, DMSO-d6) delta ppm: 1.26 (s, 12H) 7.16 (t, J=7.70 Hz,1H) 7.38 (td, J=7.85, 1.68 Hz, 1H) 7.44 (ddd, J=7.09, 5.49, 1.60 Hz, 1H)7.65 (dd, J=8.54, 2.14 Hz, 1H) 7.82 (d, J=2.14 Hz, 1H) 7.87 (d, J=8.54Hz, 1H) 10.36 (s, 1H).

4-Bromo-2-fluoro-N-[2-fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzenesulfonamide,Compound of Formula (VIII)

HRMS (ESI) calcd for C₁₈H₁₉BBrF₂NO₄S [M+Na]⁺ 495.0208, found 495.0204.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 1.27 (s, 12H) 7.14 (t, J=7.70 Hz,1H) 7.38 (td, J=7.82, 1.60 Hz, 1H) 7.44 (ddd, J=7.21, 5.30, 1.68 Hz, 1H)7.57 (dd, J=8.50, 1.80 Hz, 1H) 7.61 (dd, J=8.20, 7.60 Hz, 1H) 7.88 (dd,J=9.76, 1.68 Hz, 1H) 10.54 (s, 1H).

2-Fluoro-N-[2-fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-4-methoxy-5-methyl-benzenesulfonamide,Compound of Formula (VIII)

HRMS (ESI) calcd for C₂₀H₂₄BF₂NO₅S [M+Na]⁺ 461.1365, found 461.1362.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 1.27 (s, 12H) 2.08 (s, 3H) 3.85 (s,3H) 7.07 (d, J=12.35 Hz, 1H) 7.11 (t, J=7.70 Hz, 1H) 7.39 (t, J=6.94 Hz,2H) 7.44 (d, J=8.39 Hz, 1H) 10.19 (s, 1H).

For the following compound, the corresponding boronic acid was isolated:

(2-fluoro-3-{[(4-fluoro-2-iodophenyl)sulfonyl]amino}phenyl)boronic Acid,Compound of Formula (VIII)

HRMS (ESI) calcd for C₁₂H₉BF₂INO₄S [M+Na]⁺ 460.9286, found 460.9297.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 7.10 (t, J=7.70 Hz, 1H) 7.31 (td,J=7.85, 1.68 Hz, 1H) 7.35-7.45 (m, 2H) 7.83 (ddd, J=7.63, 4.96, 1.14 Hz,1H) 7.96 (dd, J=8.92, 5.72 Hz, 1H) 8.06 (dd, J=8.24, 2.59 Hz, 1H) 8.80(d, J=5.03 Hz, 1H) 10.29 (s, 1H).

The following compound was isolated in mixture with related boronicacid:

5-Bromo-thiophene-2-sulfonic Acid[2-fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide,Compound of Formula (VIII)

MS (ESI) for C₁₆H₁₈BBrFNO₄S₂(MW: 462.17): [M+NH₄]⁺ found 480.

Preparation 10 5-Chloro-2-fluoro-4-methoxy-benzenesulfonyl chloride,Compound of Formula (XI) Scheme 1 1-Chloro-4-fluoro-2-methoxy-benzene

To 2-chloro-5-fluoro-phenol (959 mg, 6.54 mmol) in DMF (15 mL) at 0° C.was added 60% NaH (496 mg, 12.4 mmol) portionwise. After H₂ bubblingstopped, iodomethane (0.43 mL, 6.91 mmol) was added and the reactionmixture was allowed to warm at room temperature overnight. The reactionmixture was slowly poured onto water and crushed ice, basified withsaturated aqueous NaHCO₃ and extracted with DCM. The combined organicphase was washed with brine, dried over Na₂SO₄ and evaporated undervacuum. The crude was purified by silica gel chromatography which waseluted with hexane:AcOEt=9:1 to give 1-chloro-4-fluoro-2-methoxy-benzene(600 mg) as transparent oil.

HPLC (254 nm): Rt: 6.15 min.

¹H NMR (600 MHz, DMSO-d6) delta ppm: 3.86 (s, 3H) 6.76-6.85 (m, 1H) 7.10(dd, J=10.90, 2.84 Hz, 1H) 7.45 (dd, J=8.70, 6.14 Hz, 1H).

5-Chloro-2-fluoro-4-methoxy-benzenesulfonyl chloride, Compound ofFormula (XI) Scheme 1

To 1-chloro-4-fluoro-2-methoxy-benzene (355 mg, 2.21 mmol) in DCM (20mL) at 0° C. was added chlorosulfonic acid (0.59 mL, 8.84 mmol) andstirred at room temperature overnight. The reaction was diluted withDCM, washed with water, brine, dried over Na₂SO₄ and evaporated undervacuum. The crude was purified by silica gel chromatography which waseluted with hexane:AcOEt=8:2 to furnish the title compound (400 mg) aswhite solid.

¹H NMR (600 MHz, DMSO-d6) delta ppm: 3.86 (s, 3H) 7.02 (d, J=11.17 Hz,1H) 7.59 (d, J=7.33 Hz, 1H).

Analogously the following compounds were obtained:

4,5-Dichloro-2-fluoro-benzenesulfonyl chloride, Compound of Formula (XI)

¹H NMR (500 MHz, DMSO-d6) delta ppm: 7.63 (d, J=9.00 Hz, 1H) 7.76 (d,J=6.71 Hz, 1H).

2-Fluoro-4-methoxy-5-methyl-benzenesulfonyl chloride, Compound ofFormula (XI)

¹H NMR (500 MHz, DMSO-d6) delta ppm: 2.07 (s, 3H) 3.77 (s, 3H) 6.72 (d,J=11.90 Hz, 1H) 7.39 (d, J=8.54 Hz, 1H).

4-Chloro-2-fluoro-5-methoxy-benzenesulfonyl chloride, Compound ofFormula (XI)

¹H NMR (500 MHz, DMSO-d6) delta ppm: 3.82 (s, 3H) 7.33 (d, J=6.10 Hz,1H) 7.34 (d, J=8.85 Hz, 1H).

3-Cyano-4-methoxy-benzenesulfonyl chloride, Compound of Formula (XI)

¹H NMR (500 MHz, DMSO-d6) delta ppm: 3.92 (s, 3H) 7.21 (d, J=8.85 Hz,1H) 7.76 (d, J=1.98 Hz, 1H) 7.84 (dd, J=8.69, 2.14 Hz, 1H).

3-Bromo-4-methoxy-benzenesulfonyl chloride, Compound of Formula (XI)

¹H NMR (500 MHz, DMSO-d6) delta ppm: 3.85 (s, 3H) 7.05 (d, J=8.54 Hz,1H) 7.54 (dd, J=8.46, 2.06 Hz, 1H) 7.69 (d, J=1.98 Hz, 1H).

Preparation 11N-(3-Bromo-2-cyano-phenyl)-5-chloro-2-fluoro-4-methoxy-benzenesulfonamide,Compound of Formula (XX)

To a solution of 2-amino-6-bromo-benzonitrile (501 mg, 2.47 mmol) inanhydrous DMF (20 mL) at 0° C. was added 60% NaH (176 mg, 4.4 mmol)portionwise. After 30 min, 2-Fluoro-4-methoxy-5-methyl-benzenesulfonylchloride (703 mg, 2.72 mmol) was added and the reaction mixture wasallowed to warm at room temperature. After 3 hours, the reaction wasdiluted with AcOEt, washed with saturated aqueous NH₄Cl, brine, driedover Na₂SO₄ and evaporated. The crude was purified by silica gelchromatography which was eluted with hexane:AcOEt=7:3. The resultingsolid was triturated with hexane:Et₂O=1:1 to furnish the title compound(479 mg) as white solid.

HPLC (254 nm): Rt: 5.40 min.

HRMS (ESI) calcd for C₁₄H₉BrClFN₂O₃S [M+Na]⁺ 440.9082, found 440.9075.

1H NMR (500 MHz, DMSO-d6) delta ppm: 3.87 (s, 3H) 6.81 (br. s., 1H)6.97-7.18 (m, 3H) 7.65-7.71 (m, 1H).

Preparation 124-Chloro-7-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine,Compound of Formula (XVII)A Scheme 3, Step i1A

To a solution of 4-chloro-5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine(1.16 g, 3.96 mmol) in dry THF (50 mL) at −10° C. was slowly addedi-prMgCl in THF (2.0 N, 2.4 mL, 4.80 mmol). After 5 min1-isopropoxy-3,3,4,4-tetramethyl-borolane (1.2 mL, 5.94 mmol) was addedand stirred for 2 hours. The reaction was diluted with saturated aqueousNH4Cl and extracted with AcOEt. The combined organic phase was washedwith brine, dried over Na2SO4 and evaporated. The crude was purified bysilica gel chromatography which was eluted with hexane:AcOEt=7:3 toafford4-Chloro-7-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine(850 mg) as white solid.

HPLC (254 nm): Rt: 5.99 min.

HRMS (ESI) calcd for C₁₃H₁₇BClN₃O₂[M+H]⁺ 293.1212, found 293.1221.

1H NMR (500 MHz, DMSO-d6) delta ppm: 1.30 (s, 12H) 3.84 (s, 3H) 8.04 (s,1H) 8.65 (s, 1H).

Example 1N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-3-chloro-4-methoxy-benzenesulfonamide,Compound of Formula (I), (Cmpd 1) Scheme 1

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-3-chloro-4-methoxy-N-methoxymethyl-benzenesulfonamide,Compound of Formula (X) Scheme 1, Step d

In a Schlenk tube, to5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (88 mg, 0.321mmol),3-chloro-N-[2-fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-4-methoxy-N-methoxymethyl-benzenesulfonamide(244 mg, 0.503 mmol), Cs₂CO₃ (308 mg, 0.945 mmol) and1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex withdichloromethane (1:1) (21 mg, 0.026 mmol) were added 1,2-dimethoxyethane(DME) (5 mL) and water (0.55 mL). The reaction mixture was degassed withnitrogen, heated to 85° C. for 5 hours and then filtered through acelite pad. The filtrate was evaporated under reduced pressure; thecrude was taken up with DCM, washed with saturated aqueous NaHCO₃, brineand dried over Na₂SO4. The organic was evaporated and the crude purifiedby crystallization with AcOEt to furnish the title compound (72 mg) aswhite solid.

MS (ESI) for C₂₂H₂₁ClFN₅O₄S (MW:505.96): [M+H]⁺ found 506

Analogously the following compound was obtained:

N-[3-(4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-3-chloro-4-methoxy-N-methoxymethyl-benzenesulfonamide,Compound of Formula (X)

MS (ESI) for C₂₄H₂₅ClFN₅O₄S (MW:534.01): [M+H]⁺ found 535.

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-3-chloro-4-methoxy-benzenesulfonamide,Compound of Formula (I) (Cmpd 1) Scheme 1, Step g

To a solution ofN-[3-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-3-chloro-4-methoxy-N-methoxymethyl-benzenesulfonamide(50.5 mg, 0.100 mmol) in trifluoroacetic acid (TFA) (1 mL) was addedwater (0.15 mL) and heated to 50° C. for 5 hours. The reaction mixturewas poured into a saturated aqueous NaHCO₃ and extracted with DCM. Thecombined organic phase was washed with brine, dried over Na₂SO₄ andevaporated under reduce pressure. The crude was purified by preparativeHPLC to give the title compound (20 mg) as a white solid.

HPLC (254 nm): Rt: 7.59 min.

HRMS (ESI) calcd for C₂₀H₁₇ClFN₅O₃S [M+H]⁺ 462.0798, found 462.0789.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 3.73 (s, 3H) 3.91 (s, 3H) 5.96 (br.s., 2H) 6.98-7.10 (m, 1H) 7.10-7.20 (m, 2H) 7.22 (s, 1H) 7.28 (d, J=8.79Hz, 1H) 7.68 (dd, J=8.67, 2.32 Hz, 1H) 7.75 (d, J=2.32 Hz, 1H) 8.14 (s,1H).

Analogously the following compound was obtained:

N-[3-(4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-3-chloro-4-methoxy-benzenesulfonamide,Compound of Formula (I), (Cmpd 2)

HPLC (254 nm): Rt: 5.89 min.

HRMS (ESI) calcd for C₂₂H₂₁ClFN₅O₃S [M+H]⁺ 490.1111, found 490.1114.

¹H NMR (401 MHz, DMSO-d6) delta ppm 1.44 (d, J=6.71 Hz, 6H) 3.92 (s, 3H)4.95 (spt, J=6.71 Hz, 1H) 5.95 (br. s., 2H) 7.20 (d, J=3.66 Hz, 3H)7.28-7.36 (m, 2H) 7.69 (dd, J=8.67, 2.32 Hz, 1H) 7.75 (d, J=2.32 Hz, 1H)8.13 (s, 1H) 10.18 (br. s., 1H).

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-3-chloro-4-hydroxy-benzenesulfonamide,Compound of Formula (I), (Cmpd 67) Scheme 1, Step g

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-3-chloro-4-methoxy-N-ethoxymethyl-benzenesulfonamide(9.3 mg, 0.018 mmol) in DCM (3 mL) was treated with a solution of BBr₃in DCM 1M (144 microL, 0.144 mmol) at room temperature overnight. Thereaction was quenched with MeOH and evaporated under vacuum. The crudewas purified by silica gel chromatography which was eluted withDCM:MeOH=95:5 to furnish the title compound (6.4 mg) as white solid.

HPLC (254 nm): Rt: 4.94 min.

HRMS (ESI) calcd for C₁₉H₁₅ClFN₅O₃S [M+H]⁺ 448.0641, found 448.0636.

1H NMR (401 MHz, DMSO-d6) delta ppm: 3.73 (s, 3H) 5.96 (br. s., 2H) 7.07(d, J=8.67 Hz, 1H) 7.12-7.28 (m, 4H) 7.53 (dd, J=8.67, 2.32 Hz, 1H) 7.69(d, J=2.20 Hz, 1H) 8.15 (s, 1H) 10.09 (br. s., 1H) 11.32 (br. s., 1H).

Example 2N-{3-[4-Amino-7-(1-methyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-5-chloro-2-fluoro-4-methoxy-benzenesulfonamide,Compound of Formula (I), (Cmpd 3) Scheme 1, Step c

In a Schlenk tube, to5-iodo-7-(1-methyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine(36 mg, 0.102 mmol),5-chloro-N-[2-chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-fluoro-4-methoxy-benzenesulfonamide(90 mg, 0.196 mmol), Cs₂CO₃ (119 mg, 0.365 mmol) and1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex withdichloromethane (1:1) (6.7 mg, 0.008 mmol) were added1,2-dimethoxyethane (DME) (1.8 mL) and water (0.2 mL). The reactionmixture was degassed with nitrogen, heated to 85° C. for 5 hours andthen filtered through a celite pad. The filtrate was evaporated underreduced pressure; the crude was taken up with DCM, washed with saturatedaqueous NaHCO₃, brine and dried over Na₂SO₄. The organic was evaporatedand the crude purified by silica gel chromatography which was elutedwith DCM:MeOH:NH₃=90:10:0.5% to furnish the title compound (33 mg) aswhite solid.

HPLC (254 nm): Rt: 4.85 min.

HRMS (ESI) calcd for C₂₅H₂₅ClF₂N₆O₃S [M+H]⁺ 563.1438, found 563.1445.

¹H NMR (401 MHz, DMSO-dd) delta ppm: 1.93 (m, J=12.69, 2.56 Hz, 2H)2.02-2.16 (m, 2H) 2.27 (m, J=11.41, 11.41 Hz, 2H) 2.33 (s, 3H) 3.00 (m,J=11.35 Hz, 2H) 3.93 (s, 3H) 4.58 (tt, J=11.89, 4.10 Hz, 1H) 5.98 (br.s., 2H) 7.01-7.25 (m, 3H) 7.32 (t, J=5.92 Hz, 2H) 7.70 (d, J=7.32 Hz,1H) 8.13 (s, 1H) 10.37 (s, 1H).

Analogously the following compounds were obtained:

N-{3-[4-Amino-7-(1-methyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-3-chloro-4-methoxy-benzenesulfonamide,Compound of Formula (I), (Cmpd 4)

HPLC (254 nm): Rt: 4.74 min.

HRMS (ESI) calcd for C₂₅H₂₆ClFN₆O₃S [M+H]⁺ 545.1533, found 545.1547.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 1.89 (m, J=9.52 Hz, 2H) 1.98-2.11(m, 2H) 2.11-2.21 (m, 2H) 2.27 (s, 3H) 2.94 (m, J=11.11 Hz, 2H) 3.92 (s,3H) 4.42-4.67 (m, 1H) 5.97 (br. s., 2H) 7.10-7.24 (m, 3H) 7.27-7.34 (m,2H) 7.69 (dd, J=8.67, 2.32 Hz, 1H) 7.74 (d, J=2.32 Hz, 1H) 8.12 (s, 1H)9.52-10.46 (m, 1H).

N-{3-[4-Amino-7-(1-cyclopropyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-3-chloro-4-methoxy-benzenesulfonamide,Compound of Formula (I), (Cmpd 5)

HPLC (254 nm): Rt: 5.69 min.

HRMS (ESI) calcd for C₂₇H₂₈ClFN₆O₃S [M+H]⁺ 571.1689, found 571.1685.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 0.42-1.04 (m, 4H) 2.07 (s, 3H) 2.54(br. s., 4H) 3.92 (s, 3H) 4.65-4.82 (m, 1H) 6.09 (br. s., 2H) 7.13-7.23(m, 3H) 7.28 (br. s., 1H) 7.31 (d, J=8.85 Hz, 1H) 7.71 (dd, J=8.77, 2.21Hz, 1H) 7.76 (d, J=2.29 Hz, 1H) 8.15 (s, 2H) 10.23 (br. s., 1H).

N-{3-[4-Amino-7-(1-isopropyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-3-chloro-4-methoxy-benzenesulfonamide,Compound of Formula (I), (Cmpd 6)

HPLC (254 nm): Rt: 4.93 min.

HRMS (ESI) calcd for C₂₇H₃₀ClFN₆O₃S [M+H]⁺ 573.1846, found 573.1859.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 1.03 (d, J=6.56 Hz, 6H) 1.82-2.10(m, 4H) 2.38 (d, J=14.18 Hz, 2H) 2.84 (br. s., 1H) 2.97 (m, J=9.61 Hz,2H) 3.92 (s, 3H) 4.48-4.61 (m, 1H) 5.63-6.34 (m, 2H) 7.05-7.23 (m, 3H)7.27-7.35 (m, 2H) 7.69 (dd, J=8.92, 2.06 Hz, 1H) 7.74 (d, J=2.14 Hz, 1H)8.10-8.17 (m, 1H) 9.69-10.45 (m, 1H).

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-chloro-phenyl]-5-chloro-2-fluoro-4-methoxy-benzenesulfonamide,Compound of Formula (I), (Cmpd 7)

HPLC (254 nm): Rt: 5.70 min.

HRMS (ESI) calcd for C₂₀H₁₆Cl₂FN₅O₃S [M+H]⁺ 496.0408, found 496.0417.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 3.72 (s, 3H) 3.94 (s, 3H) 5.79 (br.s., 2H) 7.23 (s, 1H) 7.25-7.45 (m, 4H) 7.70 (d, J=7.32 Hz, 1H) 8.14 (s,1H) 10.37 (br. s., 1H).

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-chloro-phenyl]-3-chloro-4-methoxy-benzenesulfonamide,Compound of Formula (I), (Cmpd 8)

HPLC (254 nm): Rt: 5.55 min.

HRMS (ESI) calcd for C₂₀H₁₇Cl₂N₅O₃S [M+H]⁺ 478.0502, found 478.05.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 3.72 (s, 3H) 3.93 (s, 3H) 5.28-6.34(m, 2H) 7.21 (s, 1H) 7.24 (d, J=7.47 Hz, 2H) 7.31 (d, J=8.85 Hz, 1H)7.33-7.39 (m, 1H) 7.67 (dd, J=8.85, 2.29 Hz, 1H) 7.79 (d, J=2.29 Hz, 1H)8.13 (s, 1H) 10.04 (s, 1H).

N-[3-(4-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenyl]-5-chloro-2-fluoro-4-methoxy-benzenesulfonamide,Compound of Formula (I), (Cmpd 9)

HPLC (254 nm): Rt: 5.34 min.

HRMS (ESI) calcd for C₁₉H₁₅ClF₂N₆O₃S [M+H]⁺ 481.0656, found 481.064.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 3.93 (s, 3H) 3.94 (s, 3H) 7.23-7.32(m, 1H) 7.33-7.41 (m, 3H) 7.73 (d, J=7.32 Hz, 1H) 8.25 (s, 1H) 10.59 (s,1H).

4-{4-Amino-3-[3-(5-chloro-2-fluoro-4-methoxy-benzenesulfonylamino)-2-fluoro-phenyl]-pyrazolo[3,4-d]pyrimidin-1-yl}-piperidine-1-carboxylicAcid tert-butyl Ester, Compound of Formula (I), (Cmpd 10)

HPLC (254 nm): Rt: 6.64 min.

HRMS (ESI) calcd for C₂₈H₃₀ClF₂N₇O₅S [M+H]⁺ 650.1759, found 650.179.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 1.42 (s, 9H) 1.83-2.05 (m, 4H) 3.00(br. s., 2H) 3.93 (s, 3H) 4.08 (m, J=13.55 Hz, 2H) 4.89 (tt, J=10.42,5.14 Hz, 1H) 7.23-7.42 (m, 4H) 7.73 (d, J=7.45 Hz, 1H) 8.24 (s, 1H)10.56 (s, 1H).

4-{4-Amino-3-[3-(3-chloro-4-methoxy-benzenesulfonylamino)-2-fluoro-phenyl]-pyrazolo[3,4-d]pyrimidin-1-yl}-piperidine-1-carboxylicAcid tert-butyl Ester, Compound of Formula (I), (Cmpd 11)

HPLC (254 nm): Rt: 6.53 min.

HRMS (ESI) calcd for C₂₈H₃₁ClFN₇O₅S [M+H]⁺ 632.1853, found 632.184.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 1.42 (s, 9H) 1.77-2.04 (m, 4H) 2.98(br. s., 2H) 3.92 (s, 3H) 4.07 (m, J=12.45 Hz, 2H) 4.89 (m, J=10.44,5.40, 5.40 Hz, 1H) 7.21-7.37 (m, 4H) 7.71 (dd, J=8.79, 2.32 Hz, 1H) 7.80(d, J=2.20 Hz, 1H) 8.23 (s, 1H) 10.24 (s, 1H).

N-[3-(4-Amino-furo[3,2-c]pyridin-3-yl)-2-fluoro-phenyl]-5-chloro-2-fluoro-4-methoxy-benzenesulfonamide,Compound of Formula (I) (Cmpd 69)

HPLC (254 nm): Rt: 6.01 min.

HRMS (ESI) calcd for C₂₀H₁₄ClF₂N₃O₄S [M+H]⁺ 466.0435, found 466.0424.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 3.94 (s, 3H) 5.42 (s, 2H) 6.95 (d,J=5.95 Hz, 1H) 7.22-7.41 (m, 4H) 7.73 (d, J=7.47 Hz, 1H) 7.87 (d, J=5.95Hz, 1H) 7.94 (s, 1H) 10.62 (br. s., 1H).

N-[3-(4-Amino-furo[3,2-c]pyridin-3-yl)-2-fluoro-phenyl]-3-chloro-4-methoxy-benzenesulfonamide,Compound of Formula (I) (Cmpd 70)

HPLC (254 nm): Rt: 5.83 min.

HRMS (ESI) calcd for C₂₀H₁₅ClFN₃O₄S [M+H]⁺ 448.0529, found 448.0519.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 3.92 (s, 3H) 5.40 (s, 2H) 6.95 (d,J=5.95 Hz, 1H) 7.20-7.35 (m, 4H) 7.68 (dd, J=8.69, 2.29 Hz, 1H) 7.78 (d,J=2.29 Hz, 1H) 7.87 (d, J=5.95 Hz, 1H) 7.92 (s, 1H) 10.31 (br. s., 1H).

N-{3-[4-Amino-7-(1-methyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-3,4-dichloro-benzenesulfonamide,Compound of Formula (I) (Cmpd 71)

HPLC (254 nm): Rt: 5.18 min.

HRMS (ESI) calcd for C₂₄H₂₃Cl₂FN₆O₂S [M+H]⁺ 549.1037, found 549.1042.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 1.95 (d, J=11.29 Hz, 2H) 2.11 (qd,J=12.70, 3.00 Hz, 2H) 2.37 (br. s, 5H) 3.06 (d, J=10.68 Hz, 2H) 4.60(tt, J=11.84, 4.02 Hz, 1H) 6.03 (br. s., 1H) 7.08 (t, J=6.70 Hz, 1H)7.13 (t, J=7.78 Hz, 1H) 7.17 (td, J=7.50, 1.70 Hz, 1H) 7.31 (s, 1H) 7.69(dd, J=8.39, 2.14 Hz, 1H) 7.83 (d, J=8.39 Hz, 1H) 7.91 (d, J=2.13 Hz,1H) 8.13 (s, 1H).

N-{3-[4-Amino-7-(1-methyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-4-bromo-2-fluoro-benzenesulfonamide,Compound of Formula (I) (Cmpd 72)

HPLC (254 nm): Rt: 4.88 min.

HRMS (ESI) calcd for C₂₄H₂₃BrF₂N₆O₂S [M+H]⁺ 577.0828, found 577.0836.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 1.95 (d, J=10.83 Hz, 2H) 2.12 (qd,J=12.20, 3.05 Hz, 2H) 2.37 (br. s, 5H) 3.06 (d, J=10.83 Hz, 2H) 4.60 (t,J=11.90 Hz, 1H) 5.98 (br. s, 2H) 7.06 (br. s., 1H) 7.11 (t, J=7.85 Hz,1H) 7.19 (td, J=7.66, 1.60 Hz, 1H) 7.32 (s, 1H) 7.55 (dd, J=8.39, 1.68Hz, 1H) 7.69 (t, J=8.08 Hz, 1H) 7.80 (d, J=9.15 Hz, 1H) 8.13 (s, 1H).

N-{3-[4-Amino-7-(1-methyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-2-fluoro-4-methoxy-5-methyl-benzenesulfonamide,Compound of Formula (I) (Cmpd 73)

HPLC (254 nm): Rt: 4.97 min.

HRMS (ESI) calcd for C₂₆H₂₈F2N₆O₃S [M+H]⁺ 543.1985, found 543.1978.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 1.88 (d, J=11.74 Hz, 2H) 2.05 (qd,J=12.10, 3.20 Hz, 2H) 2.10 (s, 3H) 2.13 (t, J=11.50 Hz, 2H) 2.25 (s, 3H)2.93 (d, J=11.13 Hz, 2H) 3.85 (s, 3H) 4.54 (tt, J=11.61, 4.18 Hz, 1H)5.98 (br. s., 2H) 7.07 (d, J=12.51 Hz, 1H) 7.13-7.19 (m, 2H) 7.19-7.26(m, 1H) 7.33 (s, 1H) 7.51 (d, J=8.24 Hz, 1H) 8.13 (s, 1H) 10.30 (br. s.,1H).

N-[3-(4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-5-chloro-2-fluoro-4-methoxy-benzenesulfonamide,Compound of Formula (I) (Cmpd 74)

HPLC (254 nm): Rt: 5.98 min.

HRMS (ESI) calcd for C₂₂H₂₀ClF₂N₅O₃S [M+H]⁺ 508.1016, found 508.1014.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 1.44 (d, J=6.86 Hz, 6H) 3.94 (s,3H) 4.95 (spt, J=6.81 Hz, 1H) 5.99 (br. s., 2H) 7.16-7.31 (m, 3H) 7.35(s, 1H) 7.38 (d, J=12.05 Hz, 1H) 7.71 (d, J=7.32 Hz, 1H) 8.13 (s, 1H)10.52 (s, 1H).

N-[3-(4-Amino-7-ethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-5-chloro-2-fluoro-4-methoxy-benzenesulfonamide,Compound of Formula (I) (Cmpd 75)

HPLC (254 nm): Rt: 8.66 min.

HRMS (ESI) calcd for C₂₁H₁₈ClF₂N₅O₃S [M+H]⁺ 494.086, found 494.0859.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 1.36 (t, J=7.24 Hz, 3H) 3.94 (s,3H) 4.19 (q, J=7.17 Hz, 2H) 6.00 (br. s., 2H) 7.17-7.28 (m, 3H) 7.31 (s,1H) 7.38 (d, J=11.90 Hz, 1H) 7.71 (d, J=7.47 Hz, 1H) 8.14 (s, 1H) 10.53(br. s., 1H).

N-{3-[4-Amino-7-(tetrahydro-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-5-chloro-2-fluoro-4-methoxy-benzenesulfonamide,Compound of Formula (I) (Cmpd 76)

HPLC (254 nm): Rt: 5.68 min.

HRMS (ESI) calcd for C₂₄H₂₂ClF₂N₅O₄S [M+H]⁺ 550.1122, found 550.1123.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 1.87 (dd, J=12.20, 2.59 Hz, 2H)1.99-2.14 (m, 2H) 3.47-3.59 (m, 2H) 3.94 (s, 3H) 3.99 (dd, J=11.21, 4.19Hz, 2H) 4.82 (tt, J=11.93, 4.08 Hz, 1H) 6.02 (br. s., 1H) 7.17-7.30 (m,3H) 7.38 (s, 1H) 7.38 (d, J=11.90 Hz, 1H) 7.71 (d, J=7.32 Hz, 1H) 8.14(s, 1H) 10.53 (s, 1H).

The following compound was isolated as TFA salt by preparative HPLC:

5-Bromo-thiophene-2-sulfonic Acid{3-[4-amino-7-(1-methyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-amide,Compound of Formula (I) (Cmpd 77)

HPLC (254 nm): Rt: 4.8 min.

HRMS (ESI) calcd for C₂₂H₂₂BrFN₆O₂S₂ [M+H]⁺ 565.0486, found 565.0497.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 2.17-2.26 (m, 2H) 2.26-2.37 (m, 2H)2.83 (br. s., 3H) 4.86 (tt, J=11.82, 4.19 Hz, 1H) 6.88 (br. s, 2H)7.24-7.33 (m, 3H) 7.35 (d, J=4.12 Hz, 1H) 7.42 (d, J=4.12 Hz, 1H) 7.44(s, 1H) 8.29 (s, 1H) 9.57 (br. s., 1H) 10.60 (br. s., 1H).

Example 3N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-4-methoxy-3-methyl-benzenesulfonamide,Compound of Formula (I), (Cmpd 12) Scheme 1

[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-carbamicAcid tert-butyl Ester, Compound of Formula (V) Scheme 1, Step a

In a Schlenk tube, to5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (395 mg, 1.442mmol),[2-fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-carbamicacid tert-butyl ester (790 mg, 2.344 mmol), Cs2CO3 (1.42 g, 4.356 mmol)and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (86.3 mg, 0.106 mmol) were added1,2-dimethoxyethane (DME) (22.5 mL) and water (2.5 mL). The reactionmixture was degassed with nitrogen, heated to 85° C. for 5 hours andthen filtered through a celite pad. The filtrate was evaporated underreduced pressure; the crude was taken up with DCM, washed with saturatedaqueous NaHCO₃, brine and dried over Na₂SO₄. The solvent was evaporatedand the crude was purified by silica gel chromatography which was elutedAcOEt to furnish the title compound (247 mg) as white solid.

HPLC (254 nm): Rt: 7.63 min.

HRMS (ESI) calcd for C₁₈H₂0FN₅O₂[M+H]⁺ 358.1674, found 358.1667.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 1.47 (s, 9H) 3.75 (s, 3H) 5.51-6.34(m, 2H) 7.06-7.15 (m, 1H) 7.20 (t, J=7.85 Hz, 1H) 7.32 (s, 1H) 7.58 (t,J=7.17 Hz, 1H) 8.15 (s, 1H) 9.05 (s, 1H).

Analogously the following compound was obtained:

[3-(4-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenyl]-carbamicAcid tert-butyl Ester, Compound of Formula (V)

HPLC (254 nm): Rt: 5.29 min.

HRMS (ESI) calcd for C₁₇H₁₉FN₆O₂[M+H]⁺ 359.1627, found 359.1631.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 1.48 (s, 9H) 3.96 (s, 3H) 6.98-7.36(m, 2H) 7.61-7.82 (m, 1H) 8.25 (s, 1H) 9.09 (s, 1H).

5-(3-Amino-2-fluoro-phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylaminehydrochloride Salt, Compound of Formula (VII) Scheme 1, Step e

[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-carbamicacid tert-butyl ester (247 mg, 0.692 mmol) was taken up in dioxane (8mL) and treated with 4M HCl in dioxane (4 mL, 16 mmol) at 40° C.overnight. The solvent was evaporated and the residue triturated withEt₂O to afford the title compound (215 mg) as hydrochloride salt.

HPLC (254 nm): Rt: 3.33 min.

HRMS (ESI) calcd for C₁₃H₁₂FN₅ [M+H]⁺ 258.115, found 258.1149.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 3.85 (s, 3H) 6.58 (t, J=6.94 Hz,1H) 6.86 (t, J=8.08 Hz, 1H) 6.94-7.05 (m, 1H) 7.63 (s, 1H) 8.47 (s, 1H).

Analogously the following compound was obtained:

3-(3-Amino-2-fluoro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine,Compound of Formula (VII)

MS (ESI) for C₁₂H₁₁FN₆ (MW: 258.26): [M+H]⁺ found 259.

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-4-methoxy-3-methyl-benzenesulfonamide,Compound of Formula (I) (Cmpd 12) Scheme 1, Step f

In a screw cap vial,5-(3-amino-2-fluoro-phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylaminehydrochloride salt (48 mg, 0.145 mmol) was suspended in DCM (4 mL).Pyridine (232 microL, 2.887 mmol) and 4-methoxy-3-methyl-benzenesulfonylchloride (64 mg, 0.290 mmol) were added and the reaction was stirred atroom temperature overnight. The mixture was diluted with DCM, washedwith saturated aqueous NaHCO₃, brine, dried over Na₂SO₄ and evaporatedunder vacuum. The crude was purified by silica gel chromatography whichwas eluted with DCM:MeOH=95:5. The solid obtained was triturated withEt₂O to afford the title compound (33 mg) as white solid.

HPLC (254 nm): Rt: 7.43 min.

HRMS (ESI) calcd for C₂₁H₂0FN₅O₃S [M+H]⁺ 442.1344, found 442.1352.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 2.15 (s, 3H) 3.73 (s, 3H) 3.84 (s,3H) 5.96 (br. s., 2H) 7.08 (d, J=8.67 Hz, 1H) 7.10-7.21 (m, 3H) 7.22 (s,1H) 7.53-7.62 (m, 2H) 8.14 (s, 1H) 10.04 (br. s., 1H).

Analogously the following compounds were obtained:

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-3-chloro-benzenesulfonamide,Compound of Formula (I), (Cmpd 13)

HPLC (254 nm): Rt: 7.46 min.

HRMS (ESI) calcd for C₁₉H₁₅ClFN₅O₂S [M+H]⁺ 432.0692, found 432.0695.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 3.76 (s, 3H) 6.45 (br. s., 2H)7.12-7.26 (m, 3H) 7.32 (s, 1H) 7.59-7.64 (m, 1H) 7.69-7.77 (m, 2H)7.78-7.81 (m, 1H) 8.23 (s, 1H) 10.40 (br. s., 1H).

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-4-methoxy-benzenesulfonamide,Compound of Formula (I), (Cmpd 14)

HPLC (254 nm): Rt: 6.44 min.

HRMS (ESI) calcd for C₂₀H₁₈FN₅O₃S [M+H]⁺ 428.1187, found 428.1196.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 3.73 (s, 3H) 3.81 (s, 3H) 5.95 (br.s., 2H) 7.08 (d, J=8.91 Hz, 2H) 7.13-7.28 (m, 4H) 7.70 (d, J=8.91 Hz,2H) 8.15 (s, 1H) 10.07 (s, 1H).

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide,Compound of Formula (I), (Cmpd 15)

HPLC (254 nm): Rt: 8.35 min.

HRMS (ESI) calcd for C₂₀H₁₅F₄N₅O₂S [M+H]⁺ 466.0956, found 466.0955.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 3.70-3.79 (m, 3H) 6.61 (br. s., 2H)7.14-7.26 (m, 3H) 7.31 (s, 1H) 7.90-8.04 (m, 4H) 8.25 (s, 1H) 10.52 (br.s., 1H).

Pyridine-3-sulfonic acid[3-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-amide,Compound of Formula (I), (Cmpd 16)

HPLC (254 nm): Rt: 4.34 min.

HRMS (ESI) calcd for C₁₈H₁₅FN₆O₂S [M+H]⁺ 399.1034, found 399.1029.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 3.72 (s, 3H) 5.96 (br. s., 2H)6.99-7.34 (m, 4H) 7.63 (ddd, J=8.06, 4.88, 0.73 Hz, 1H) 8.13 (m, J=2.32,1.59 Hz, 1H) 8.14 (s, 1H) 8.82 (dd, J=4.76, 1.59 Hz, 1H) 8.86-9.00 (m,1H) 10.49 (br. s., 1H).

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-3,4-dimethoxy-benzenesulfonamide,Compound of Formula (I), (Cmpd 17)

HPLC (254 nm): Rt: 4.89 min.

HRMS (ESI) calcd for C₂₁H₂₀FN₅O₄S [M+H]⁺ 458.1293, found 458.1304.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 3.73 (s, 3H) 3.73 (s, 3H) 3.81 (s,3H) 5.95 (br. s., 2H) 7.09 (d, J=8.54 Hz, 1H) 7.13-7.21 (m, 3H) 7.22 (s,1H) 7.27 (d, J=2.20 Hz, 1H) 7.33 (dd, J=8.48, 2.14 Hz, 1H) 8.15 (s, 1H)10.03 (s, 1H).

4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonic acid[3-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-amide,Compound of Formula (I), (Cmpd 18)

HPLC (254 nm): Rt: 5.24 min.

HRMS (ESI) calcd for C₂₂H₂₁FN₆O₃S [M+H]⁺ 469.1453, found 469.1463.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 2.78 (s, 3H) 3.24-3.28 (m, 2H) 3.73(s, 3H) 4.19-4.34 (m, 2H) 5.95 (br. s., 2H) 6.78 (d, J=8.91 Hz, 1H)6.96-7.01 (m, 1H) 6.98 (s, 1H) 7.12-7.25 (m, 3H) 7.23 (s, 1H) 8.15 (s,1H) 9.96 (s, 1H).

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-4-nitro-benzenesulfonamide,Compound of Formula (I), (Cmpd 19)

HPLC (254 nm): Rt: 5.21 min.

HRMS (ESI) calcd for C₁₉H₁₅FN₆O₄S [M+H]⁺ 443.0933, found 443.0944.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 3.72 (s, 3H) 5.97 (br. s., 2H)7.15-7.29 (m, 4H) 7.98-8.06 (m, 2H) 8.14 (s, 1H) 8.35-8.44 (m, 2H) 10.63(br. s., 1H).

Naphthalene-2-sulfonic acid[3-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-amide,Compound of Formula (I), (Cmpd 20)

HPLC (254 nm): Rt: 5.62 min.

HRMS (ESI) calcd for C₂₃H₁₈FN₅O₂S [M+H]⁺ 448.1238, found 448.1242.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 3.68 (s, 3H) 5.92 (br. s., 2H) 7.08(s, 1H) 7.10-7.27 (m, 3H) 7.62-7.68 (m, 1H) 7.68-7.75 (m, 1H) 7.82 (dd,J=8.73, 1.89 Hz, 1H) 8.03 (d, J=8.18 Hz, 1H) 8.13 (t, J=4.27 Hz, 3H)8.40 (d, J=1.46 Hz, 1H) 10.33 (s, 1H).

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-2,5-difluoro-benzenesulfonamide,Compound of Formula (I), (Cmpd 21)

HPLC (254 nm): Rt: 5.21 min.

HRMS (ESI) calcd for C₁₉H₁₄F3N₅O₂S [M+H]⁺ 434.0893, found 434.0901.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 3.73 (s, 3H) 5.96 (br. s., 2H)7.13-7.32 (m, 4H) 7.51-7.67 (m, 3H) 8.15 (s, 1H) 10.70 (br. s., 1H).

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-4-bromo-2-fluoro-benzenesulfonamide,Compound of Formula (I), (Cmpd 22)

HPLC (254 nm): Rt: 5.57 min.

HRMS (ESI) calcd for C₁₉H₁₄BrF₂N₅O₂S [M+H]⁺ 494.0093, found 494.0105.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 3.73 (s, 3H) 5.96 (br. s., 2H)7.09-7.32 (m, 4H) 7.59 (dd, J=8.42, 1.59 Hz, 1H) 7.65-7.73 (m, 1H) 7.88(dd, J=10.01, 1.34 Hz, 1H) 8.15 (s, 1H) 10.64 (br. s., 1H).

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-2,6-difluoro-benzenesulfonamideCompound of Formula (I), (Cmpd 23)

HPLC (254 nm): Rt: 5.01 min.

HRMS (ESI) calcd for C₁₉H₁₄F3N₅O₂S [M+H]⁺ 434.0893, found 434.0902.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 3.74 (br. s., 3H) 5.92 (br. s., 2H)7.05-7.37 (m, 6H) 7.65-7.78 (m, 1H) 8.15 (s, 1H) 10.82 (br. s., 1H).

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-5-chloro-2-fluoro-4-methoxy-benzenesulfonamide,Compound of Formula (I), (Cmpd 24)

HPLC (254 nm): Rt: 5.56 min.

HRMS (ESI) calcd for C₂₀H₁₆ClF₂N₅O₃S [M+H]⁺ 480.0703, found 480.0711.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 3.71-3.76 (m, 3H) 3.94 (s, 3H) 5.98(br. s., 2H) 7.15-7.28 (m, 4H) 7.36 (d, J=12.08 Hz, 1H) 7.71 (d, J=7.45Hz, 1H) 8.15 (s, 1H) 10.50 (s, 1H).

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-3,4-dichloro-benzenesulfonamide,Compound of Formula (I), (Cmpd 25)

HPLC (254 nm): Rt: 5.85 min.

HRMS (ESI) calcd for C₁₉H₁₄Cl₂FN₅O₂S [M+H]⁺ 466.0302, found 466.0309.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 3.73 (s, 3H) 6.00 (br. s., 2H)7.10-7.27 (m, 4H) 7.71 (dd, J=8.48, 2.14 Hz, 1H) 7.88 (d, J=8.42 Hz, 1H)7.95 (d, J=2.07 Hz, 1H) 8.15 (s, 1H) 10.45 (br. s., 1H).

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-3,5-dichloro-benzenesulfonamide,Compound of Formula (I), (Cmpd 26)

HPLC (254 nm): Rt: 5.91 min.

HRMS (ESI) calcd for C₁₉H₁₄Cl₂FN₅O₂S [M+H]⁺ 466.0302, found 466.0304.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 3.73 (s, 3H) 6.00 (br. s., 2H)7.13-7.30 (m, 4H) 7.73 (d, J=1.95 Hz, 2H) 7.96 (t, J=1.71 Hz, 1H) 8.15(s, 1H) 10.52 (br. s., 1H).

2,3-Dihydro-benzofuran-5-sulfonic Acid[3-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-amide,Compound of Formula (I), (Cmpd 27)

HPLC (254 nm): Rt: 5.08 min.

HRMS (ESI) calcd for C₂₁H₁₈FN₅O₃S [M+H]⁺ 440.1187, found 440.1205.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 3.21 (t, J=8.79 Hz, 2H) 3.73 (s,3H) 4.62 (t, J=8.85 Hz, 2H) 5.96 (br. s., 2H) 6.89 (d, J=8.42 Hz, 1H)7.10-7.23 (m, 3H) 7.24 (s, 1H) 7.53 (dd, J=8.54, 2.08 Hz, 1H) 7.63 (d,J=1.71 Hz, 1H) 8.15 (s, 1H) 10.01 (s, 1H).

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-4-ethoxy-3-methyl-benzenesulfonamide,Compound of Formula (I), (Cmpd 28)

HPLC (254 nm): Rt: 10.44 min.

HRMS (ESI) calcd for C₂₂H₂₂FN₅O₃S [M+H]⁺ 456.15, found 456.1511.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 1.34 (t, J=6.96 Hz, 3H) 2.15 (s,3H) 3.73 (s, 3H) 4.09 (q, J=6.96 Hz, 2H) 5.95 (br. s., 2H) 7.02-7.09 (m,1H) 7.12-7.20 (m, 3H) 7.22 (s, 1H) 7.52-7.60 (m, 2H) 8.15 (s, 1H) 10.00(s, 1H).

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-4-methoxy-3,5-dimethyl-benzenesulfonamide,Compound of Formula (I), (Cmpd 29)

HPLC (254 nm): Rt: 5.55 min.

HRMS (ESI) calcd for C₂₂H₂₂FN₅O₃S [M+H]⁺ 456.15, found 456.1505.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 2.24 (s, 6H) 3.68 (s, 3H) 3.73 (s,3H) 5.97 (br. s., 2H) 7.09-7.21 (m, 3H) 7.23 (s, 1H) 7.47 (s, 2H) 8.15(s, 1H) 10.08 (s, 1H).

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-4-isopropoxy-3-methyl-benzenesulfonamide,Compound of Formula (I), (Cmpd 30)

HPLC (254 nm): Rt: 7.93 min.

HRMS (ESI) calcd for C23H24FN5O3S [M+H]⁺ 470.1657, found 470.1643.

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-3,4-dimethyl-benzenesulfonamide,Compound of Formula (I), (Cmpd 31)

HPLC (254 nm): Rt: 5.55 min.

HRMS (ESI) calcd for C₂₁H₂₀FN₅O₂S [M+H]⁺ 426.1395, found 426.1385.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 2.25 (s, 3H) 2.27 (s, 3H) 3.72 (s,3H) 5.98 (br. s., 2H) 7.06-7.20 (m, 3H) 7.23 (s, 1H) 7.32 (d, J=7.93 Hz,1H) 7.44-7.51 (m, 1H) 7.55 (s, 1H) 8.14 (s, 1H) 10.15 (s, 1H).

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-3,4,5-trifluoro-benzenesulfonamide,Compound of Formula (I), (Cmpd 32)

HPLC (254 nm): Rt: 5.56 min.

HRMS (ESI) calcd for C₁₉H₁₃F4N₅O₂S [M+H]⁺ 452.0799, found 452.0786.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 3.73 (s, 3H) 6.04 (br. s., 2H)7.10-7.24 (m, 3H) 7.27 (s, 1H) 7.74 (t, J=6.56 Hz, 2H) 8.15 (s, 1H)10.54 (br. s., 1H).

5-Bromo-6-chloro-pyridine-3-sulfonic Acid[3-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-amide,Compound of Formula (I), (Cmpd 33)

HPLC (254 nm): Rt: 5.49 min.

HRMS (ESI) calcd for C₁₈H₁₃BrClFN₆O₂S [M+H]⁺ 510.975, found 510.9738.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 3.73 (s, 3H) 6.07 (br. s., 2H)7.12-7.27 (m, 4H) 8.15 (s, 1H) 8.49 (d, J=2.14 Hz, 1H) 8.72 (d, J=2.29Hz, 1H) 10.65 (br. s., 1H).

N-[3-(4-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenyl]-4-methoxy-3-methyl-benzenesulfonamide,Compound of Formula (I), (Cmpd 34)

HPLC (254 nm): Rt: 5.23 min.

HRMS (ESI) calcd for C₂₀H₁₉FN₆O₃S [M+H]⁺ 443.1296, found 443.1299.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 2.15 (s, 3H) 3.84 (s, 3H) 3.93 (s,3H) 7.07 (d, J=8.67 Hz, 1H) 7.20-7.26 (m, 1H) 7.26-7.36 (m, 2H) 7.57 (d,J=1.59 Hz, 1H) 7.61 (dd, J=8.54, 2.32 Hz, 1H) 8.24 (s, 1H) 10.07 (s,1H).

N-[3-(4-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenyl]-3-chloro-4-methoxy-benzenesulfonamide,Compound of Formula (I) (Cmpd 35)

HPLC (254 nm): Rt: 5.22 min.

HRMS (ESI) calcd for C₁₉H₁₆ClFN₆O₃S [M+H]⁺ 463.075, found 463.0749.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 3.92 (s, 3H) 3.93 (s, 3H) 7.23-7.28(m, 1H) 7.28-7.36 (m, 3H) 7.71 (dd, J=8.67, 2.32 Hz, 1H) 7.81 (d, J=2.32Hz, 1H) 8.24 (s, 1H) 10.24 (s, 1H).

Example 4N-{3-[4-Amino-7-(tetrahydro-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-4-methoxy-3-methyl-benzenesulfonamide,Compound of Formula (I) (Cmpd 36) Scheme 1

5-(3-Amino-2-fluoro-phenyl)-7-(tetrahydro-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine,Compound of Formula (VII) Scheme 1, Step b

In a Schlenk tube, to5-iodo-7-(tetrahydro-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine(70 mg, 0.203 mmol),2-fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine(104 mg, 0.439 mmol), Cs₂CO₃ (250 mg, 0.767 mmol) and1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex withdichloromethane (1:1) (14 mg, 0.017 mmol) were added 1,2-dimethoxyethane(DME) (3.6 mL) and water (0.4 mL). The reaction mixture was degassedwith nitrogen, heated to 85° C. for 5 hours and then filtered through acelite pad. The filtrate was evaporated under reduced pressure; thecrude was taken up with DCM, washed with saturated aqueous NaHCO₃, brineand dried over Na₂SO₄. The solvent was evaporated and the crude waspurified by silica gel chromatography which was eluted withDCM:MeOH=95:5. The solid obtained was triturated with Et₂O to afford thetitle compound (39 mg) as white solid.

HPLC (254 nm): Rt: 4.30 min.

HRMS (ESI) calcd for C₁₇H₁₈FN₅O [M+H]⁺ 328.1568, found 328.1575.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 1.87 (dd, J=12.33, 2.44 Hz, 2H)2.02-2.18 (m, 2H) 3.53 (t, J=11.17 Hz, 2H) 4.00 (dd, J=11.23, 4.03 Hz,2H) 4.83 (tt, J=11.93, 3.94 Hz, 1H) 5.23 (br. s., 2H) 5.99 (br. s., 2H)6.41-6.61 (m, 1H) 6.77 (td, J=8.24, 1.59 Hz, 1H) 6.88-7.02 (m, 1H) 7.42(s, 1H) 8.13 (s, 1H).

Analogously the following compounds were obtained:

5-(3-Amino-2-fluoro-phenyl)-7-(1-methyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine,Compound of Formula (VII)

HPLC (254 nm): Rt: 3.32 min.

HRMS (ESI) calcd for C₁₈H₂₁FN₆ [M+H]⁺ 341.1885, found 341.1895.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 1.77-1.96 (m, 2H) 2.00-2.15 (m, 4H)2.22 (s, 3H) 2.79-3.00 (m, 2H) 4.42-4.63 (m, 1H) 5.22 (s, 2H) 5.97 (br.s., 2H) 6.52 (ddd, J=7.50, 6.70, 1.60 Hz, 1H) 6.77 (td, J=8.21, 1.65 Hz,1H) 6.95 (ddd, J=7.90, 7.50, 0.60 Hz, 1H) 7.37 (s, 1H) 8.12 (s, 1H).

5-(3-Amino-2-fluoro-phenyl)-7-(1-isopropyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine,Compound of Formula (VII)

MS (ESI) for C₂₀H₂₅FN₆ (MW: 368.46): [M+H]⁺ found 369.

5-(3-Amino-2-fluoro-phenyl)-7-(1-cyclopropyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine,Compound of Formula (VII)

MS (ESI) for C₂₀H₂₆FN₆ (MW: 366.24): [M+H]⁺ found 367.

4-[4-Amino-5-(3-amino-2-fluoro-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-piperidine-1-carboxylicAcid tert-butyl Ester, Compound of Formula (VII)

HPLC (254 nm): Rt: 5.69 min.

HRMS (ESI) calcd for C₂₂H₂₇FN₆O₂[M+H]⁺ 427.2253, found 427.2245.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 1.42 (s, 9H) 1.84-2.01 (m, 4H) 2.94(br. s., 2H) 4.11 (br. s., 2H) 4.67-4.80 (m, 1H) 5.25 (s, 2H) 6.51 (t,J=6.48 Hz, 1H) 6.76 (t, J=7.55 Hz, 1H) 6.94 (t, J=7.85 Hz, 1H) 7.43 (s,1H) 8.12 (s, 1H).

5-(3-Amino-2-fluoro-phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine,Compound of Formula (VII)

HPLC (254 nm): Rt: 4.03 min.

HRMS (ESI) calcd for C₁₃H₁₂FN₅ [M+H]⁺ 258.115, found 258.1154.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 3.74 (s, 3H) 5.26 (s, 2H) 5.76 (s,2H) 6.45-6.57 (m, 1H) 6.76 (td, J=8.24, 1.53 Hz, 1H) 6.87-7.00 (m, 1H)7.27 (s, 1H) 8.14 (s, 1H).

5-(3-Amino-2-methyl-phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine,Compound of Formula (VII)

HPLC (254 nm): Rt: 4.05 min.

HRMS (ESI) calcd for C₁₄H₁₅N₅[M+H]⁺ 254.14, found 254.1397.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 1.92 (s, 3H) 3.73 (s, 3H) 4.95-5.06(m, 2H) 5.11-6.29 (m, 2H) 6.46 (dd, J=7.32, 0.92 Hz, 1H) 6.61-6.71 (m,1H) 6.87-6.98 (m, 1H) 7.07 (s, 1H) 8.11 (s, 1H).

5-(3-Amino-2-chloro-phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine,Compound of Formula (VII)

HPLC (254 nm): Rt: 4.25 min.

HRMS (ESI) calcd for C₁₃H₁₂ClN₅ [M+H]⁺ 274.0854, found 274.0852.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 3.74 (s, 3H) 5.50 (s, 2H) 5.55-6.38(m, 2H) 6.56 (dd, J=7.47, 1.53 Hz, 1H) 6.83 (dd, J=8.16, 1.60 Hz, 1H)7.08 (t, J=7.70 Hz, 1H) 7.21 (s, 1H) 8.13 (s, 1H).

N-{3-[4-Amino-7-(tetrahydro-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-4-methoxy-3-methyl-benzenesulfonamide,Compound of Formula (I) (Cmpd 36) Scheme 1, Step f

To5-(3-amino-2-fluoro-phenyl)-7-(tetrahydro-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine(15 mg, 0.046 mmol) in DCM (1.5 mL) were added pyridine (6 microL, 0.074mmol) and 4-methoxy-3-methyl-benzenesulfonyl chloride (14 mg, 0.063mmol). The reaction was stirred at room temperature overnight. Then thereaction was diluted with DCM, washed with saturated aqueous NaHCO₃,brine, dried over Na₂SO₄ and evaporated. The crude was purified bysilica gel chromatography which was eluted with DCM:MeOH=95:5 to furnishthe title compound (24 mg) as white solid.

HPLC (254 nm): Rt: 5.54 min.

HRMS (ESI) calcd for C₂₅H₂₆FN₅O₄S [M+H]⁺ 512.1763, found 512.1758.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 1.87 (dd, J=12.14, 2.62 Hz, 2H)1.97-2.13 (m, 2H) 2.15 (s, 3H) 3.52 (m, J=11.11, 11.11 Hz, 2H) 3.85 (s,3H) 3.99 (dd, J=11.35, 4.15 Hz, 2H) 4.82 (tt, J=11.92, 3.89 Hz, 1H) 5.97(br. s., 2H) 7.09 (d, J=8.79 Hz, 1H) 7.13-7.24 (m, 3H) 7.33 (s, 1H) 7.54(d, J=1.71 Hz, 1H) 7.59 (dd, J=8.67, 2.20 Hz, 1H) 8.13 (s, 1H) 10.00 (s,1H).

Analogously the following compounds were obtained:

N-{3-[4-Amino-7-(tetrahydro-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-3-chloro-4-methoxy-benzenesulfonamide,Compound of Formula (I) (Cmpd 37)

HPLC (254 nm): Rt: 5.55 min.

HRMS (ESI) calcd for C₂₄H₂₃ClFN₅O₄S [M+H]⁺ 532.1216, found 532.1213.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 1.87 (dd, J=12.08, 2.44 Hz, 2H)1.96-2.13 (m, 2H) 3.45-3.61 (m, 2H) 3.93 (s, 3H) 3.99 (dd, J=11.29, 4.09Hz, 2H) 4.82 (tt, J=11.90, 4.09 Hz, 1H) 5.99 (br. s., 2H) 7.11-7.25 (m,3H) 7.28-7.36 (m, 2H) 7.70 (dd, J=8.67, 2.32 Hz, 1H) 7.75 (d, J=2.32 Hz,1H) 8.13 (s, 1H) 10.18 (s, 1H).

N-{3-[4-Amino-7-(1-methyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-4-methoxy-3-methyl-benzenesulfonamide,Compound of Formula (I) (Cmpd 38)

HPLC (254 nm): Rt: 4.85 min.

HRMS (ESI) calcd for C₂₆H₂₉FN₆O₃S [M+H]⁺ 525.2079, found 525.207.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 1.89 (d, J=10.99 Hz, 2H) 2.05 (qd,J=12.08, 3.28 Hz, 2H) 2.15 (br. s, 2H) 2.15 (s, 3H) 2.27 (br. s., 3H)2.94 (d, J=9.46 Hz, 2H) 3.84 (s, 3H) 4.55 (tt, J=11.88, 4.06 Hz, 1H)5.99 (br. s., 2H) 7.09 (d, J=8.70 Hz, 1H) 7.13-7.23 (m, 3H) 7.30 (s, 1H)7.54 (dd, J=2.37, 0.69 Hz, 1H) 7.59 (dd, J=8.62, 2.37 Hz, 1H) 8.12 (s,1H) 10.01 (br. s., 1H).

N-{3-[4-Amino-7-(1-cyclopropyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-4-methoxy-3-methyl-benzenesulfonamide,Compound of Formula (I) (Cmpd 39)

HPLC (254 nm): Rt: 5.69 min.

HRMS (ESI) calcd for C₂₈H₃₁FN₆O₃S [M+H]⁺ 551.2235, found 551.2244.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 0.27-0.35 (m, 2H) 0.39-0.51 (m, 2H)1.62-1.73 (m, 1H) 1.79-1.90 (m, 2H) 1.95 (qd, J=12.02, 3.58 Hz, 2H) 2.14(s, 3H) 2.30-2.42 (m, 2H) 3.05 (d, J=11.44 Hz, 2H) 3.83 (s, 3H) 4.56(tt, J=11.90, 3.97 Hz, 1H) 5.96 (br. s., 2H) 7.08 (d, J=8.85 Hz, 1H)7.11-7.23 (m, 3H) 7.28 (s, 1H) 7.52 (dd, J=2.44, 0.76 Hz, 1H) 7.58 (dd,J=8.54, 2.29 Hz, 1H) 8.12 (s, 1H) 10.04 (br. s., 1H).

N-{3-[4-Amino-7-(1-isopropyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-4-methoxy-3-methyl-benzenesulfonamide,Compound of Formula (I), (Cmpd 40)

HPLC (254 nm): Rt: 5.03 min.

HRMS (ESI) calcd for C₂₈H₃₃FN₆O₃S [M+H]⁺ 553.2392, found 553.2408.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 1.00 (d, J=6.56 Hz, 6H) 1.84-1.93(m, 2H) 1.98 (qd, J=11.90, 2.90 Hz, 2H) 2.14 (s, 3H) 2.25-2.35 (m, 2H)2.76 (spt, J=6.60 Hz, 1H) 2.92 (d, J=11.59 Hz, 2H) 3.84 (s, 3H) 4.51(tt, J=11.93, 4.31 Hz, 1H) 5.96 (br. s., 2H) 7.06 (d, J=8.69 Hz, 2H)7.11 (t, J=7.70 Hz, 1H) 7.18 (td, J=7.90, 1.70 Hz, 1H) 7.29 (s, 1H) 7.52(d, J=1.68 Hz, 1H) 7.58 (dd, J=8.62, 2.21 Hz, 1H) 8.12 (s, 1H) 9.86 (br.s, 1H).

N-{3-[4-Amino-7-(1-ethyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-4-methoxy-3-methyl-benzenesulfonamide,Compound of Formula (I), (Cmpd 41)

HPLC (254 nm): Rt: 4.72 min.

HRMS (ESI) calcd for C₂₇H₃₁FN₆O₃S [M+H]⁺ 539.2235, found 539.2239.

4-{4-Amino-5-[2-fluoro-3-(4-methoxy-3-methyl-benzenesulfonylamino)-phenyl]-pyrrolo[2,3-d]pyrimidin-7-yl}-piperidine-1-carboxylicAcid tert-butyl Ester, Compound of Formula (I), (Cmpd 42)

MS (ESI) for C₃₀H₃₅FN₆O₅S (MW:610.71): [M+H]⁺ found 611.

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-4,5-dichloro-2-fluoro-benzenesulfonamide,Compound of Formula (I), (Cmpd 43)

HPLC (254 nm): Rt: 5.84 min.

HRMS (ESI) calcd for C₁₉H₁₃Cl₂F₂N₅O₂S [M+H]⁺ 484.0208, found 484.0219.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 3.73 (s, 3H) 6.05 (br. s., 2H)7.14-7.30 (m, 4H) 7.93 (d, J=6.86 Hz, 1H) 8.05 (d, J=9.61 Hz, 1H) 8.16(s, 1H) 10.84 (br. s., 1H).

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-2-fluoro-4-methoxy-5-methyl-benzenesulfonamide,Compound of Formula (I), (Cmpd 44)

HPLC (254 nm): Rt: 5.52 min.

HRMS (ESI) calcd for C₂₁H₁₉F2N₅O₃S [M+H]⁺ 460.125, found 460.1243.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 2.10 (s, 3H) 3.73 (s, 3H) 3.85 (s,3H) 5.99 (br. s., 2H) 7.08 (d, J=12.35 Hz, 1H) 7.14-7.24 (m, 3H) 7.25(s, 1H) 7.51 (d, J=8.08 Hz, 1H) 8.15 (s, 1H) 10.30 (s, 1H).

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-2,5-dichloro-benzenesulfonamide,Compound of Formula (I), (Cmpd 45)

HPLC (254 nm): Rt: 5.67 min.

HRMS (ESI) calcd for C₁₉H₁₄Cl₂FN₅O₂S [M+H]⁺ 466.0302, found 466.0294.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 3.73 (s, 3H) 5.97 (br. s., 2H)7.18-7.25 (m, 3H) 7.26 (s, 1H) 7.67-7.78 (m, 2H) 7.92 (dd, J=2.08, 0.85Hz, 1H) 8.15 (s, 1H) 10.67 (br. s., 1H).

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-4-bromo-2,5-difluoro-benzenesulfonamide,Compound of Formula (I), (Cmpd 46)

HPLC (254 nm): Rt: 5.65 min.

HRMS (ESI) calcd for C₁₉H₁₃BrF₃N₅O₂S [M+H]⁺ 511.9998, found 511.9978.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 3.73 (s, 3H) 5.98 (br. s., 2H)7.10-7.30 (m, 4H) 7.73 (dd, J=7.63, 6.04 Hz, 1H) 8.06 (dd, J=9.03, 5.37Hz, 1H) 8.15 (s, 1H) 10.77 (br. s., 1H).

5-Chloro-thiophene-2-sulfonic Acid[3-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-amide,Compound of Formula (I), (Cmpd 47)

HPLC (254 nm): Rt: 5.46 min.

HRMS (ESI) calcd for C₁₇H₁₃ClFN₅O₂S₂ [M+H]⁺ 438.0256, found 438.0244.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 3.74 (s, 3H) 5.99 (br. s., 2H)7.07-7.33 (m, 5H) 7.43 (d, J=4.03 Hz, 1H) 8.15 (s, 1H) 10.57 (br. s.,1H).

5-Bromo-thiophene-2-sulfonic Acid[3-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-amide,Compound of Formula (I), (Cmpd 48)

HPLC (254 nm): Rt: 5.50 min.

HRMS (ESI) calcd for C₁₇H₁₃BrFN₅O₂S₂ [M+H]⁺ 481.9751, found 481.9739.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 3.74 (s, 3H) 5.99 (br. s., 2H) 7.25(d, J=5.13 Hz, 4H) 7.31-7.36 (m, 1H) 7.36-7.41 (m, 1H) 8.15 (s, 1H)10.56 (br. s., 1H).

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-3,5-bis-trifluoromethyl-benzenesulfonamide,Compound of Formula (I), (Cmpd 49)

HPLC (254 nm): Rt: 6.17 min.

HRMS (ESI) calcd for C₂₁H₁₄F₇N₅O₂S [M+H]⁺ 534.0829, found 534.0824.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 3.72 (s, 3H) 6.01 (br. s., 2H)7.12-7.30 (m, 4H) 8.14 (s, 1H) 8.30 (s, 2H) 8.51 (s, 1H) 10.67 (br. s.,1H).

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-3-chloro-4-trifluoromethoxy-benzenesulfonamide,Compound of Formula (I), (Cmpd 50)

HPLC (254 nm): Rt: 6.14 min.

HRMS (ESI) calcd for C₂₀H₁₄ClF₄N₅O₃S [M+H]⁺ 516.0515, found 516.0507.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 3.72 (s, 3H) 6.01 (br. s., 2H)7.04-7.29 (m, 4H) 7.72-7.88 (m, 2H) 8.02 (d, J=2.07 Hz, 1H) 8.15 (s, 1H)10.50 (br. s., 1H).

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-4-bromo-3-trifluoromethyl-benzenesulfonamide,Compound of Formula (I), (Cmpd 51)

HPLC (254 nm): Rt: 6.03 min.

HRMS (ESI) calcd for C₂₀H₁₄BrF₄N₅O₂S [M+H]⁺ 544.0061, found 544.0071.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 3.73 (s, 3H) 6.01 (br. s., 2H)7.05-7.31 (m, 4H) 7.91 (dd, J=8.36, 2.26 Hz, 1H) 8.09 (d, J=2.20 Hz, 1H)8.11-8.17 (m, 2H) 10.53 (br. s., 1H).

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-4-bromo-3-methyl-benzenesulfonamide,Compound of Formula (I), (Cmpd 52)

HPLC (254 nm): Rt: 5.83 min.

HRMS (ESI) calcd for C₂₀H₁₇BrFN₅O₂S [M+H]⁺ 490.0343, found 490.033.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 2.39 (s, 3H) 3.73 (s, 3H) 5.98 (br.s., 2H) 6.97-7.34 (m, 4H) 7.41-7.59 (m, 1H) 7.74 (d, J=1.95 Hz, 1H) 7.81(d, J=8.42 Hz, 1H) 8.15 (s, 1H) 10.29 (s, 1H).

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-3-fluoro-4-methoxy-benzenesulfonamide,Compound of Formula (I), (Cmpd 53)

HPLC (254 nm): Rt: 5.19 min.

HRMS (ESI) calcd for C₂₀H₁₇F2N₅O₃S [M+H]⁺ 446.1093, found 446.1084.

¹H NMR (401 MHz, DMSO-d6) delta ppm: 3.73 (s, 3H) 3.90 (s, 3H) 5.97 (br.s., 2H) 7.16-7.21 (m, 3H) 7.23 (s, 1H) 7.30-7.36 (m, 1H) 7.53-7.62 (m,2H) 8.15 (s, 1H) 10.18 (s, 1H).

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-4-bromo-benzenesulfonamide,Compound of Formula (I), (Cmpd 54)

HPLC (254 nm): Rt: 7.95 min.

HRMS (ESI) calcd for C₁₉H₁₅BrFN₅O₂S [M+H]⁺ 476.0187, found 476.0184.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 3.72 (s, 3H) 5.99 (br. s., 2H)7.14-7.23 (m, 3H) 7.21 (s, 1H) 7.65-7.71 (m, 2H) 7.80 (d, J=8.69 Hz, 2H)8.14 (s, 1H) 10.37 (br. s., 1H).

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-4-chloro-benzenesulfonamide,Compound of Formula (I), (Cmpd 55)

HPLC (254 nm): Rt: 7.70 min.

HRMS (ESI) calcd for C₁₉H₁₅ClFN₅O₂S [M+H]⁺ 432.0692, found 432.0701.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 3.72 (s, 3H) 5.99 (br. s., 2H) 7.22(s, 1H) 7.13-7.24 (m, 3H) 7.62-7.69 (m, 2H) 7.73-7.80 (m, 2H) 8.14 (s,1H) 10.37 (br. s., 1H).

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-4-iodo-benzenesulfonamide,Compound of Formula (I), (Cmpd 56)

HPLC (254 nm): Rt: 8.32 min.

HRMS (ESI) calcd for C₁₉H₁₅FIN₅O₂S [M+H]⁺ 524.0048, found 524.0042.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 3.73 (s, 3H) 6.06 (br. s., 2H)7.15-7.23 (m, 3H) 7.22 (s, 1H) 7.49-7.54 (m, 2H) 7.92-8.01 (m, 2H) 8.16(s, 1H) 10.34 (s, 1H).

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-methanesulfonamide,Compound of Formula (I), (Cmpd 68)

HPLC (254 nm): Rt: 4.02 min.

HRMS (ESI) calcd for C₁₄H₁₄FN₅O₂S [M+H]⁺ 336.0925, found 336.0921.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 3.05 (s, 3H) 3.75 (s, 3H) 6.07 (br.s., 2H) 7.17-7.23 (m, 1H) 7.25 (t, J=7.80 Hz, 1H) 7.34 (s, 1H) 7.37 (td,J=7.63, 1.83 Hz, 1H) 8.15 (s, 1H) 9.67 (br. s, 1H).

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methyl-phenyl]-5-chloro-2-fluoro-4-methoxy-benzenesulfonamide,Compound of Formula (I), (Cmpd 57)

HPLC (254 nm): Rt: 5.63 min.

HRMS (ESI) calcd for C₂₁H₁₉ClFN₅O₃S [M+H]⁺ 476.0954, found 476.095.

1H NMR (500 MHz, DMSO-d6) delta ppm: 2.03 (s, 3H) 3.72 (s, 3H) 3.95 (s,3H) 5.06-6.53 (m, 2H) 6.99 (dd, J=7.85, 1.45 Hz, 1H) 7.09-7.18 (m, 2H)7.19 (d, J=7.63 Hz, 1H) 7.37 (d, J=11.90 Hz, 1H) 7.66 (d, J=7.32 Hz, 1H)8.13 (s, 1H) 10.00 (s, 1H).

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methyl-phenyl]-3-chloro-4-methoxy-benzenesulfonamide,Compound of Formula (I), (Cmpd 58)

HPLC (254 nm): Rt: 5.50 min.

HRMS (ESI) calcd for C₂₁H₂₀ClN₅O₃S [M+H]⁺ 458.1048, found 458.105.

1H NMR (500 MHz, DMSO-d6) delta ppm: 1.95 (s, 3H) 3.72 (s, 3H) 3.93 (s,3H) 5.08-6.41 (m, 2H) 6.91 (dd, J=7.85, 1.30 Hz, 1H) 7.03-7.15 (m, 2H)7.17 (d, J=7.78 Hz, 1H) 7.31 (d, J=8.85 Hz, 1H) 7.57 (dd, J=8.69, 2.29Hz, 1H) 7.70 (d, J=2.14 Hz, 1H) 8.12 (s, 1H) 9.67 (br. s., 1H).

Propane-1-sulfonic Acid[3-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-amide,Compound of Formula (I) (Cmpd 78)

HPLC (254 nm): Rt: 4.65 min.

HRMS (ESI) calcd for C₁₆H₁₈FN₅O₂S [M+H]⁺ 364.1238, found 364.1232.

1H NMR (500 MHz, DMSO-d6) delta ppm: 0.98 (t, J=7.47 Hz, 3H) 1.76 (sxt,J=7.53 Hz, 2H) 3.10-3.18 (m, 2H) 3.77 (s, 3H) 6.34 (br. s., 2H)7.19-7.29 (m, 2H) 7.36-7.44 (m, 2H) 8.20 (s, 1H) 9.69 (s, 1H).

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-4-chloro-2-fluoro-5-methoxy-benzenesulfonamide,Compound of Formula (I) (Cmpd 79)

HPLC (254 nm): Rt: 5.43 min.

HRMS (ESI) calcd for C₂₀H₁₆ClF₂N₅O₃S [M+H]⁺ 480.0703, found 480.07.

1H NMR (401 MHz, DMSO-d6) delta ppm: 3.73 (s, 3H) 3.83 (s, 3H) 5.65-6.18(m, 2H) 7.07-7.21 (m, 1H) 7.23 (s, 1H) 7.36-7.43 (m, 1H) 8.14 (s, 1H).

5-Methyl-thiophene-2-sulfonic acid[3-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-amide,Compound of Formula (I) (Cmpd 80)

HPLC (254 nm): Rt: 5.1 min.

HRMS (ESI) calcd for C₁₈H₁₆FN₅O₂S₂ [M+H]⁺ 418.0802, found 418.0806.

1H NMR (500 MHz, DMSO-d6) delta ppm: 2.47 (d, J=0.76 Hz, 3H) 3.73 (s,3H) 5.96 (br. s., 2H) 6.87 (dq, J=3.79, 1.02 Hz, 1H) 7.17-7.30 (m, 3H)7.26 (s, 1H) 7.36 (d, J=3.81 Hz, 1H) 8.15 (s, 1H) 10.35 (s, 1H).

6-Methoxy-pyridine-3-sulfonic Acid[3-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-amide,Compound of Formula (I) (Cmpd 81)

HPLC (254 nm): Rt: 4.84 min.

HRMS (ESI) calcd for C₁₉H₁₇FN₆O₃S [M+H]⁺ 429.114, found 429.1146.

1H NMR (500 MHz, DMSO-d6) delta ppm: 3.72 (s, 3H) 3.91 (s, 3H) 6.01 (br.s., 2H) 7.01 (dd, J=8.85, 0.61 Hz, 1H) 7.17-7.25 (m, 3H) 7.23 (s, 1H)8.00 (dd, J=8.77, 2.67 Hz, 1H) 8.14 (s, 1H) 8.51 (dd, J=2.59, 0.61 Hz,1H) 10.32 (s, 1H).

3-Methyl-3H-imidazole-4-sulfonic Acid[3-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-amide,Compound of Formula (I) (Cmpd 82)

HPLC (254 nm): Rt: 3.78 min.

HRMS (ESI) calcd for C₁₇H₁₆FN₇O₂S [M+H]⁺ 402.1143, found 402.114.

1H NMR (500 MHz, DMSO-d6) delta ppm: 3.67 (s, 3H) 3.74 (s, 3H) 5.98 (br.s., 2H) 7.13-7.17 (m, 1H) 7.16-7.21 (m, 1H) 7.29 (s, 1H) 7.36 (td,J=7.44, 2.21 Hz, 1H) 7.77 (d, J=1.22 Hz, 1H) 7.80 (d, J=0.92 Hz, 1H)8.15 (s, 1H) 10.05 (s, 1H).

Furan-2-sulfonic Acid[3-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-amide,Compound of Formula (I) (Cmpd 83)

HPLC (254 nm): Rt: 5.22 min.

HRMS (ESI) calcd for C₁₇H₁₄FN₅O₃S [M+H]⁺ 388.0874, found 388.0884.

1H NMR (500 MHz, DMSO-d6) delta ppm: 3.74 (s, 3H) 5.98 (br. s., 2H) 6.66(dd, J=3.43, 1.75 Hz, 1H) 7.09 (d, J=3.36 Hz, 1H) 7.18-7.27 (m, 3H) 7.28(s, 1H) 8.00 (dd, J=1.68, 0.76 Hz, 1H) 8.15 (s, 1H) 10.58 (br. s., 1H).

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-benzenesulfonamide,Compound of Formula (I) (Cmpd 84)

HPLC (254 nm): Rt: 4.91 min.

HRMS (ESI) calcd for C₁₉H₁₆FN₅O₂S [M+H]⁺ 398.1082, found 398.1087.

1H NMR (500 MHz, DMSO-d6) delta ppm: 3.72 (s, 3H) 5.94 (br. s., 2H)7.12-7.25 (m, 3H) 7.21 (s, 1H) 7.53-7.61 (m, 2H) 7.61-7.69 (m, 1H)7.73-7.80 (m, 2H) 8.14 (s, 1H) 10.27 (s, 1H).

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-4-chloro-2-fluoro-benzenesulfonamide,Compound of Formula (I) (Cmpd 85)

HPLC (254 nm): Rt: 5.47 min.

HRMS (ESI) calcd for C₁₉H₁₄ClF₂N₅O₂S [M+H]⁺ 450.0598, found 450.0593.

1H NMR (500 MHz, DMSO-d6) delta ppm: 3.73 (s, 3H) 5.99 (br. s., 2H)7.19-7.28 (m, 4H) 7.46 (dd, J=8.54, 1.83 Hz, 1H) 7.73-7.81 (m, 2H) 8.15(s, 1H) 10.67 (br. s., 1H).

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-3-cyano-4-methoxy-benzenesulfonamide,Compound of Formula (I) (Cmpd 86)

HPLC (254 nm): Rt: 5.01 min.

HRMS (ESI) calcd for C₂₁H₁₇FN₆O₃S [M+H]⁺ 453.114, found 453.1136.

1H NMR (500 MHz, DMSO-d6) delta ppm: 3.73 (s, 3H) 3.99 (s, 3H) 6.03 (br.s., 2H) 7.13-7.23 (m, 3H) 7.24 (s, 1H) 7.43 (d, J=9.15 Hz, 1H) 8.01 (dd,J=9.00, 2.29 Hz, 1H) 8.10 (d, J=2.44 Hz, 1H) 8.15 (s, 1H) 10.30 (s, 1H).

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-3-bromo-4-methoxy-benzenesulfonamide,Compound of Formula (I) (Cmpd 87)

HPLC (254 nm): Rt: 5.47 min.

HRMS (ESI) calcd for C₂₀H₁₇BrFN₅O₃S [M+H]⁺ 506.0292, found 506.0297.

1H NMR (500 MHz, DMSO-d6) delta ppm: 3.73 (s, 3H) 3.91 (s, 3H) 6.01 (br.s., 2H) 7.14-7.22 (m, 3H) 7.23 (s, 1H) 7.27 (d, J=8.85 Hz, 1H) 7.73 (dd,J=8.69, 2.29 Hz, 1H) 7.91 (d, J=2.29 Hz, 1H) 8.15 (s, 1H) 10.21 (s, 1H).

For the following compounds, pyridine was used as solvent:

Cyclopropanesulfonic Acid[3-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-amide,Compound of Formula (I) (Cmpd 88)

HPLC (254 nm): Rt: 4.43 min.

HRMS (ESI) calcd for C₁₆H₁₆FN₅O₂S [M+H]⁺ 362.1082, found 362.1079.

1H NMR (500 MHz, DMSO-d6) delta ppm: 0.86-0.94 (m, 2H) 0.93-1.01 (m, 2H)2.67-2.75 (m, 1H) 3.75 (s, 3H) 6.05 (br. s., 2H) 7.21-7.30 (m, 2H) 7.35(s, 1H) 7.37-7.44 (m, 1H) 8.15 (s, 1H) 9.67 (s, 1H).

Cyclohexanesulfonic Acid[3-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-amide,Compound of Formula (I) (Cmpd 89)

HPLC (254 nm): Rt: 5.3 min.

HRMS (ESI) calcd for C₁₉H₂₂FN₅O₂S [M+H]⁺ 404.1551, found 404.1548.

1H NMR (500 MHz, DMSO-d6) delta ppm: 1.14 (tt, J=12.80, 3.00 Hz, 1H)1.26 (qt, J=12.70, 3.15 Hz, 2H) 1.42 (qd, J=12.38, 3.13 Hz, 2H) 1.61 (d,J=12.20 Hz, 1H) 1.78 (dt, J=12.96, 3.13 Hz, 2H) 2.11 (d, J=10.83 Hz, 2H)3.06 (tt, J=11.71, 3.09 Hz, 1H) 3.75 (s, 3H) 6.06 (br. s., 2H) 7.18-7.23(m, 1H) 7.22-7.26 (m, 1H) 7.33 (s, 1H) 7.41 (td, J=7.51, 2.21 Hz, 1H)8.15 (s, 1H) 9.64 (s, 1H).

N-[3-(4-Amino-thieno[3,2-c]pyridin-3-yl)-2-fluoro-phenyl]-5-chloro-2-fluoro-4-methoxy-benzenesulfonamide,Compound of Formula (I), (Cmpd 59) Scheme 1

3-(3-Amino-2-fluoro-phenyl)-thieno[3,2-c]pyridin-4-ylamine, Compound ofFormula (VII) Scheme 1, Step b

To a solution of 3-bromo-thieno[3,2-c]pyridin-4-ylamine (80 mg, 0.35mmol) in DME (3.2 mL) and water (0.32 mL), Cs₂CO₃ (342 mg, 1.05 mmol)and2-fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine(207 mg, 0.87 mmol) were added. The mixture was sonicated for 5 minutesbefore adding Pd(dppf)Cl₂ (20 mg) and microwave heating at 100° C. for1.5 h. The mixture was diluted with AcOEt and washed with a saturatedsolution of NaHCO₃ and brine. The organic layer was dried with Na₂SO₄and evaporated to dryness. The residue was purified by flash columnchromatography over silica gel eluting with DCM-MeOH 2%.3-(3-amino-2-fluoro-phenyl)-thieno[3,2-c]pyridin-4-ylamine was soisolated (68 mg).

HPLC (254 nm): Rt: 4.55 min.

HRMS (ESI) calcd for C₁₃H₁₁FN₃S [M+H]⁺ 260.0652, found 260.0654.

1H NMR (500 MHz, DMSO-d6) delta ppm 5.38 (s, 4H) 6.52 (ddd, J=7.44,6.37, 1.45 Hz, 1H) 6.88 (td, J=8.27, 1.60 Hz, 1H) 6.99 (t, J=7.70 Hz,1H) 7.26 (d, J=5.64 Hz, 1H) 7.51 (s, 1H) 7.81 (d, J=5.64 Hz, 1H).

N-[3-(4-Amino-thieno[3,2-c]pyridin-3-yl)-2-fluoro-phenyl]-5-chloro-2-fluoro-4-methoxy-benzenesulfonamide,Compound of Formula (I) (Cmpd 59) Scheme 1, Step f

To a solution of3-(3-amino-2-fluoro-phenyl)-thieno[3,2-c]pyridin-4-ylamine (40 mg, 0.15mmol) in DCM (2.5 mL), pyridine (15 microL) and5-chloro-2-fluoro-4-methoxy sulfonyl chloride (50 mg, 0.19 mmol) wereadded. The mixture was stirred at room temperature for 1 day and then atreflux for 15 hours. After diluting with DCM, the solution was washedwith a saturated solution of NaHCO₃ and water. The organic layer wasthen dried with Na₂SO₄ and evaporated to dryness. The residue waspurified by flash column chromatography over silica gel eluting with agradient of 1:1-4:6 hexane/AcOEt, yielding the title compound (12.3 mg).

HPLC (254 nm): Rt: 6.20 min.

HRMS (ESI) calcd for C₂₀H₁₅ClF₂N₃O₃S₂[M+H]⁺ 482.0206, found 482.0202.

1H NMR (500 MHz, DMSO-d6) delta ppm 3.93 (s, 3H) 5.15-5.32 (m, 2H)7.23-7.33 (m, 3H) 7.38 (d, J=11.90 Hz, 1H) 7.39-7.44 (m, 1H) 7.52 (s,1H) 7.73 (d, J=7.32 Hz, 1H) 7.83 (d, J=5.64 Hz, 1H) 10.67 (br. s., 1H)

Analogously the following compound was obtained:

N-[3-(4-Amino-thieno[3,2-c]pyridin-3-yl)-2-fluoro-phenyl]-4-methoxy-3-methyl-benzenesulfonamide,Compound of Formula (I), (Cmpd 60)

HPLC (254 nm): Rt: 6.15 min.

HRMS (ESI) calcd for C₂₁H₁₉FN₃O₃S₂ [M+H]⁺ 444.0847, found 444.0847.

1H NMR (500 MHz, DMSO-d6) delta ppm 2.19 (s, 3H) 3.87 (s, 3H) 5.22 (br.s., 2H) 7.12 (d, J=8.39 Hz, 1H) 7.22-7.30 (m, 2H) 7.32 (d, J=5.64 Hz,1H) 7.41 (td, J=7.32, 2.59 Hz, 1H) 7.53 (s, 1H) 7.57-7.61 (m, 2H) 7.86(d, J=5.64 Hz, 1H) 10.19 (br. s., 1H).

Example 5N-{3-[4-Amino-1-(1-methyl-piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl}-5-chloro-2-fluoro-4-methoxy-benzenesulfonamide,Compound of Formula (I), (Cmpd 61) Scheme 1

N-[3-(4-Amino-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenyl]-5-chloro-2-fluoro-4-methoxy-benzenesulfonamide,Compound of Formula (I), (Cmpd 62) Scheme 1

To4-{4-amino-3-[3-(5-chloro-2-fluoro-4-methoxy-benzenesulfonylamino)-2-fluoro-phenyl]-pyrazolo[3,4-d]pyrimidin-1-yl}-piperidine-1-carboxylicacid tert-butyl ester (155 mg, 0.239 mmol) in dioxane (4 mL) was addedHCl in dioxane 4M (4 mL, 16 mmol) and stirred at room temperatureovernight. The organic was removed under vacuum and the residue taken upwith water and treated with aqueous NaOH 2N until pH of the solutionwas >9. The resulting solid was filtered and triturated with Et₂O tofurnish the title compound (100 mg) as white solid.

HPLC (254 nm): Rt: 4.64 min.

HRMS (ESI) calcd for C₂₃H₂₂ClF₂N₇O₃S [M+H]⁺ 550.1234, found 550.1238.

1H NMR (401 MHz, DMSO-d6) delta ppm: 1.92 (m, J=10.74 Hz, 2H) 2.03-2.24(m, 2H) 2.80 (td, J=12.42, 1.65 Hz, 2H) 3.18 (m, J=12.57 Hz, 2H) 3.86(s, 3H) 4.81 (tt, J=11.52, 4.23 Hz, 1H) 6.62 (td, J=6.87, 1.53 Hz, 1H)6.88 (t, J=7.69 Hz, 1H) 7.05 (d, J=11.35 Hz, 1H) 7.18 (td, J=8.27, 1.65Hz, 1H) 7.68-7.72 (m, 1H) 8.21 (s, 1H).

Analogously the following compounds were obtained:

N-[3-(4-Amino-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenyl]-3-chloro-4-methoxy-benzenesulfonamide,Compound of Formula (I), (Cmpd 63)

HPLC (254 nm): Rt: 4.57 min.

HRMS (ESI) calcd for C₂₃H₂₃ClFN₇O₃S [M+H]⁺ 532.1329, found 532.1341.

1H NMR (401 MHz, DMSO-d6) delta ppm: 1.97-2.07 (m, 2H) 2.12-2.29 (m, 2H)3.01 (td, J=12.76, 2.56 Hz, 2H) 3.88 (s, 3H) 4.94 (tt, J=11.31, 4.32 Hz,1H) 6.81 (t, J=6.77 Hz, 1H) 6.98 (t, J=7.81 Hz, 1H) 7.18 (d, J=8.67 Hz,1H) 7.21-7.27 (m, 1H) 7.67 (dd, J=8.54, 2.20 Hz, 1H) 7.69-7.72 (m, 1H)8.22-8.24 (m, 1H).

N-[3-(4-Amino-7-piperidin-4-yl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-4-methoxy-3-methyl-benzenesulfonamide,Compound of Formula (I), (Cmpd 64)

HPLC (254 nm): Rt: 4.79 min.

HRMS (ESI) calcd for C₂₅H₂₇FN₆O₃S [M+H]⁺ 511.1922, found 511.1918.

1H NMR (500 MHz, DMSO-d6) delta ppm: 2.11-2.18 (m, 5H) 2.23-2.34 (m, 2H)3.06-3.21 (m, 2H) 3.85 (s, 3H) 4.91-5.01 (m, 1H) 7.09 (d, J=8.69 Hz, 1H)7.17-7.28 (m, 4H) 7.55 (s, 2H) 7.60 (d, J=1.83 Hz, 1H) 7.65 (dd, J=8.62,2.36 Hz, 1H) 8.45 (s, 1H) 8.78 (m, J=9.46 Hz, 1H) 8.99 (d, J=9.91 Hz,1H) 10.12 (s, 1H).

N-{3-[4-Amino-1-(1-methyl-piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl}-5-chloro-2-fluoro-4-methoxy-benzenesulfonamide,Compound of Formula (I) (Cmpd 61) Scheme 1

ToN-[3-(4-amino-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenyl]-5-chloro-2-fluoro-4-methoxy-benzenesulfonamide(26 mg, 0.047 mmol) in DCM (2 mL) was added formaldehyde solution inwater 37% (21 microL, 0.280 mmol), AcOH (3 microL, 0.052 mmol) andstirred 10 min at room temperature. Then NaBH(OAc)₃ (66 mg, 0.302 mmol)was added and the mixture was stirred at room temperature for 5 h. Thereaction was diluted with DCM and treated with saturated aqueous NaHCO₃.The aqueous layer was extracted with DCM and the combined organic phasewashed with brine, dried over Na₂SO₄ and evaporated. The crude waspurified by silica gel chromatography which was eluted withDCM:MeOH:NH₃=95:5:0.5% to furnish the title compound (17 mg) as whitesolid.

HPLC (254 nm): Rt: 4.75 min.

HRMS (ESI) calcd for C₂₄H₂₄ClF₂N₇O₃S [M+H]⁺ 564.1391, found 564.1385.

1H NMR (401 MHz, DMSO-d6) delta ppm: 1.98 (m, J=10.86 Hz, 2H) 2.14-2.31(m, 2H) 2.34-2.48 (m, 5H) 3.10 (m, J=10.86 Hz, 2H) 3.91 (s, 3H) 4.74 (m,J=11.11, 11.11 Hz, 1H) 4.70-4.70 (m, 0H) 7.18 (d, J=6.47 Hz, 2H)7.22-7.38 (m, 2H) 7.73 (d, J=7.45 Hz, 1H) 8.23 (s, 1H) 9.37-10.81 (m,1H).

Analogously the following compounds were obtained:

N-{3-[4-Amino-1-(1-isopropyl-piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl}-5-chloro-2-fluoro-4-methoxy-benzenesulfonamide,Compound of Formula (I), (Cmpd 65)

HPLC (254 nm): Rt: 4.99 min.

HRMS (ESI) calcd for C₂₆H₂₈ClF₂N₇O₃S [M+H]⁺ 592.1704, found 592.1702.

1H NMR (401 MHz, DMSO-d6) delta ppm: 1.09-1.19 (m, 6H) 2.07 (br. s., 2H)2.27 (m, J=9.89 Hz, 2H) 2.70-3.25 (m, 5H) 3.91 (s, 3H) 4.84 (br. s., 1H)7.15 (br. s., 2H) 7.20-7.35 (m, 2H) 7.73 (d, J=7.45 Hz, 1H) 8.13-8.33(m, 1H).

N-{3-[4-Amino-1-(1-methyl-piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl}-3-chloro-4-methoxy-benzenesulfonamide,Compound of Formula (I), (Cmpd 66)

HPLC (254 nm): Rt: 4.61 min.

HRMS (ESI) calcd for C₂₄H₂₅ClFN₇O₃S [M+H]⁺ 546.1485, found 546.1485.

1H NMR (500 MHz, DMSO-d6) delta ppm: 1.93 (m, J=10.98 Hz, 2H) 2.12-2.24(m, 2H) 2.26-2.42 (m, 5H) 3.02 (m, J=9.00 Hz, 2H) 3.91 (s, 3H) 4.59-4.79(m, 1H) 7.07-7.36 (m, 4H) 7.71 (dd, J=8.77, 2.21 Hz, 1H) 7.79 (d, J=2.29Hz, 1H) 8.22 (s, 1H) 9.58-10.49 (m, 1H).

Example 6N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-cyano-phenyl]-5-chloro-2-fluoro-4-methoxy-benzenesulfonamide,Compound of Formula (I), (Cmpd 90) Scheme 2

5-Chloro-N-[3-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-cyano-phenyl]-2-fluoro-4-methoxy-benzenesulfonamide,Compound of Formula (XIV) Scheme 2, Step c3

In a Schlenk tube, to4-chloro-7-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine(118 mg, 0.403 mmol),N-(3-bromo-2-cyano-phenyl)-5-chloro-2-fluoro-4-methoxy-benzenesulfonamide(85 mg, 0.202 mmol), Cs₂CO₃ (217 mg, 0.666 mmol) and1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex withdichloromethane (1:1) (17 mg, 0.020 mmol) were added DMF (5 mL). Thereaction mixture was degassed with nitrogen, heated to 100° C. overnightand then filtered through a celite pad. The filtrate was evaporatedunder reduced pressure; the crude was taken up with DCM, washed withsaturated aqueous NaHCO₃, brine and dried over Na₂SO₄. The organic wasevaporated and the crude purified by silica gel chromatography which waseluted with AcOEt:hexane=7:3 to furnish the title compound (40 mg) aswhite solid.

HPLC (254 nm): Rt: 5.55 min.

HRMS (ESI) calcd for C₂₁H₁₄Cl₂FN₅O₃S [M+H]⁺ 506.0251, found 506.0251.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 3.92 (s, 3H) 3.95 (s, 3H) 7.22-7.35(m, 1H) 7.38 (d, J=11.90 Hz, 1H) 7.44-7.54 (m, 1H) 7.63 (d, J=7.32 Hz,1H) 7.70 (t, J=7.85 Hz, 1H) 7.96 (s, 1H) 8.72 (s, 1H) 11.00 (br. s.,1H).

N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-cyano-phenyl]-5-chloro-2-fluoro-4-methoxy-benzenesulfonamide,Compound of Formula (I), (cmpd 90) Scheme 2, Step h1

To a 5 mL microwave vial charged with dioxane (0.5 mL) was added5-chloro-N-[3-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-cyano-phenyl]-2-fluoro-4-methoxy-benzenesulfonamide(21 mg, 0.041 mmol), ammonium hydroxide (2.5 mL, 19.11 mmol) and sealed.The reaction vessel was heated under microwave irradiation for 180 minat 130° C. The mixture was diluted with water and extracted with DCM.The combined organic phase was washed with brine, dried over Na₂SO₄ andevaporated. The solid obtained was triturated with Et₂O to afford thetitle compound (6.8 mg) as white solid.

HPLC (254 nm): Rt: 4.79 min.

HRMS (ESI) calcd for C₂₁H₁₆ClFN₅O₃S [M+H]⁺ 487.075, found 487.0754.

¹H NMR (500 MHz, DMSO-d6) delta ppm: 3.74 (s, 3H) 3.87 (s, 3H) 4.93-6.30(m, 1H) 6.51 (d, J=6.86 Hz, 1H) 7.08-7.16 (m, 1H) 7.16-7.23 (m, 1H) 7.31(s, 1H) 7.74 (d, J=7.32 Hz, 1H) 8.14 (s, 1H).

1-24. (canceled)
 25. A compound of formula (I)

wherein n is 0, 1 or 2; R1 is an optionally substituted group selectedfrom straight or branched (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8)alkynyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkenyl, heterocyclyl, aryland heteroaryl; R2 and R3 are independently halogen, cyano, OR4 or anoptionally substituted group selected from straight or branched (C1-C8)alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl and (C3-C8) cycloalkyl, whereinR4 is an optionally substituted group selected from straight or branched(C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl and (C3-C8) cycloalkyl;E1 and E2 are independently CH or N; A is O, S or NR5, wherein R5 ishydrogen or an optionally substituted group selected from straight orbranched (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C8)cycloalkyl, (C3-C8) cycloalkenyl, heterocyclyl, aryl and heteroaryl; ora pharmaceutically acceptable salt thereof.
 26. A compound orpharmaceutically acceptable salt according to claim 25, wherein n is 0or 1; R1 is an optionally substituted group selected from (C3-C8)cycloalkyl, aryl and heteroaryl; R2 is halogen or (C1-C8) alkyl; and Ais S or NR5, wherein R5 is hydrogen or an optionally substituted groupselected from straight or branched (C1-C8) alkyl, (C2-C8) alkenyl,(C2-C8) alkynyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkenyl, heterocyclyl,aryl and heteroaryl.
 27. A compound or pharmaceutically acceptable saltaccording to claim 26, wherein n is 0; R1 is an optionally substitutedaryl or heteroaryl; R2 is halogen; and A is NR5, wherein R5 is hydrogenor an optionally substituted group selected from straight or branched(C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C8) cycloalkyl,(C3-C8) cycloalkenyl, heterocyclyl, aryl and heteroaryl.
 28. A compoundor pharmaceutically acceptable salt according to claim 27, wherein R1 isan optionally substituted aryl and A is NR5, wherein R5 is an optionallysubstituted group selected from straight or branched (C1-C8) alkyl and(C3-C8) cycloalkyl.
 29. A compound, which is selected from the groupconsisting of:N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-3-chloro-4-methoxy-benzenesulfonamide(cmpd 1);N-[3-(4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-3-chloro-4-methoxy-benzenesulfonamide(cmpd 2);N-{3-[4-Amino-7-(1-methyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-5-chloro-2-fluoro-4-methoxy-benzenesulfonamide(cmpd 3);N-{3-[4-Amino-7-(1-methyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-3-chloro-4-methoxy-benzenesulfonamide(cmpd 4);N-{3-[4-Amino-7-(1-cyclopropyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-3-chloro-4-methoxy-benzenesulfonamide(cmpd 5);N-{3-[4-Amino-7-(1-isopropyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-3-chloro-4-methoxy-benzenesulfonamide(cmpd 6);N-[3-(4-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenyl]-5-chloro-2-fluoro-4-methoxy-benzenesulfonamide(cmpd 9);N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-4-methoxy-3-methyl-benzenesulfonamide(cmpd 12);N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-3-chloro-benzenesulfonamide(cmpd 13);N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-4-bromo-2-fluoro-benzenesulfonamide(cmpd 22);N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-5-chloro-2-fluoro-4-methoxy-benzenesulfonamide(cmpd 24);N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-3,4-dichloro-benzenesulfonamide(cmpd 25);N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-3,5-dichloro-benzenesulfonamide(cmpd 26);N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-4-methoxy-3,5-dimethyl-benzenesulfonamide(cmpd 29);N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-3,4,5-trifluoro-benzenesulfonamide(cmpd 32); 5-Bromo-6-chloro-pyridine-3-sulfonic acid[3-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-amide(cmpd 33);N-[3-(4-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenyl]-4-methoxy-3-methyl-benzenesulfonamide(cmpd 34);N-[3-(4-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenyl]-3-chloro-4-methoxy-benzenesulfonamide(cmpd 33);N-{3-[4-Amino-7-(tetrahydro-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-4-methoxy-3-methyl-benzenesulfonamide(cmpd 36);N-{3-[4-Amino-7-(tetrahydro-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-3-chloro-4-methoxy-benzenesulfonamide(cmpd 37);N-{3-[4-Amino-7-(1-methyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-4-methoxy-3-methyl-benzenesulfonamide(cmpd 38);N-{3-[4-Amino-7-(1-cyclopropyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-4-methoxy-3-methyl-benzenesulfonamide(cmpd 39);N-{3-[4-Amino-7-(1-isopropyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-4-methoxy-3-methyl-benzenesulfonamide(cmpd 40);N-{3-[4-Amino-7-(1-ethyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-4-methoxy-3-methyl-benzenesulfonamide(cmpd 41);N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-2-fluoro-4-methoxy-5-methyl-benzenesulfonamide(cmpd 44);N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-4-bromo-2,5-difluoro-benzenesulfonamide(cmpd 46); 5-Chloro-thiophene-2-sulfonic acid[3-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-amide(cmpd 47); 5-Bromo-thiophene-2-sulfonic acid[3-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-amide(cmpd 48);N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-4-bromo-3-methyl-benzenesulfonamide(cmpd 52);N-{3-[4-Amino-1-(1-methyl-piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl}-5-chloro-2-fluoro-4-methoxy-benzenesulfonamide(cmpd 61);N-[3-(4-Amino-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenyl]-5-chloro-2-fluoro-4-methoxy-benzenesulfonamide(cmpd 62);N-[3-(4-Amino-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenyl]-3-chloro-4-methoxy-benzenesulfonamide(cmpd 63);N-[3-(4-Amino-7-piperidin-4-yl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-4-methoxy-3-methyl-benzenesulfonamide(cmpd 64);N-{3-[4-Amino-7-(1-methyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-3,4-dichloro-benzenesulfonamide(cmpd 71);N-{3-[4-Amino-7-(1-methyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-4-bromo-2-fluoro-benzenesulfonamide(cmpd 72);N-{3-[4-Amino-7-(1-methyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-2-fluoro-4-methoxy-5-methyl-benzenesulfonamide(cmpd 73); 6-Methoxy-pyridine-3-sulfonic acid[3-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-amide(cmpd 81);N-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-4-chloro-2-fluoro-benzenesulfonamide(cmpd 85) andN-[3-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-3-bromo-4-methoxy-benzenesulfonamide(cmpd 87), or a pharmaceutically acceptable salt of said compound.
 30. Aprocess for preparing a compound or pharmaceutically acceptable saltaccording to claim 25, which comprises the step of cross-coupling of anintermediate of formula (II)

wherein E1 and E2 are independently CH or N; A is O, S or NR5, whereinR5 is hydrogen or an optionally substituted group selected from straightor branched (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C8)cycloalkyl, (C3-C8) cycloalkenyl, heterocyclyl, aryl and heteroaryl; andX is halogen or a leaving group, alternatively with the followingcompounds: Step a) a derivative of formula (IV)

wherein R2 and R3 are independently halogen, cyano, OR4 or an optionallysubstituted group selected from straight or branched (C1-C8) alkyl,(C2-C8) alkenyl, (C2-C8) alkynyl and (C3-C8) cycloalkyl, wherein R4 isan optionally substituted group selected from straight or branched(C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl and (C3-C8) cycloalkyl;n is 0, 1 or 2; M is an organometal group and Pg is a nitrogenprotecting group; followed by Step e) selective removing of the Pg groupfrom the resultant intermediate of formula (V)

wherein E1, E2, A, R2, R3, n and Pg are as defined above; and Step f)reacting the resultant intermediate of formula (VII)

wherein E1, E2, A, R2, R3 and n are as defined above, with a derivativeof formula (XI)

wherein R1 is as defined in claim 1, to obtain a compound of formula (I)

as defined in claim 25; OR: Step b) a derivative of formula (VI)

wherein R2, R3, n and M are as defined above; followed by Step f)reacting the resultant intermediate of formula (VII), as defined above,with a derivative of formula (XI), as defined above, to obtain acompound of formula (I)

as defined in claim 25; OR: Step c) a derivative of formula (VIII)

wherein R1, R2, R3, n and M are as defined above; OR: Step d) aderivative of formula (IX)

wherein R1, R2, R3, n, Pg and M are as defined above; followed by: Stepg) selective removing of the Pg group from the resultant intermediate offormula (X)

wherein E1, E2, A, R1, R2, R3, n and Pg are as defined above, to obtaina compound of formula (I)

as defined in claim 25; optionally converting said compound of formula(I) into another compound of formula (I), converting said compound offormula (I) into a pharmaceutically acceptable salt thereof, orconverting said salt into a free compound (I).
 31. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundor pharmaceutically acceptable salt according to claim 25, and at leastone pharmaceutically acceptable excipient, carrier and/or diluent. 32.The pharmaceutical composition according to claim 31, further comprisingone or more chemotherapeutic agents.
 33. A method for treating a diseasecaused by and/or associated with a dysregulated protein kinase activitywhich comprises administering to a mammal in need thereof an effectiveamount of a compound or pharmaceutically acceptable salt according toclaim
 25. 34. The method according to claim 33, which is for treating adisease caused by and/or associated with a dysregulated protein kinaseRNA-like ER kinase activity.
 35. The method according to claim 33,wherein said mammal in need thereof is a human.
 36. The method accordingto claim 33, wherein said disease is selected from the group consistingof cancer, a cell proliferative disorder, a viral infection, anautoimmune disorder and a neurodegenerative disorder.
 37. The methodaccording to claim 36, wherein said cancer is selected from the groupconsisting of carcinoma; hematopoietic tumors of lymphoid lineage;tumors of mesenchymal origin; melanoma; seminoma; teratocarcinoma;osteosarcoma; xeroderma pigmentosum; keratoxanthoma; thyroid follicularcancer; and Kaposi's sarcoma.
 38. The method according to claim 36,wherein said cell proliferative disorder is selected from the groupconsisting of benign prostate hyperplasia, familial adenomatosispolyposis, neurofibromatosis, psoriasis, vascular smooth cellproliferation associated with atherosclerosis, pulmonary fibrosis,arthritis, glomerulonephritis, and post-surgical stenosis andrestenosis.
 39. The method according to claim 36, wherein said viralinfection is HIV infection and said method is for the prevention of AIDSdevelopment in an HIV-infected individual.
 40. The method according toclaim 36, wherein said autoimmune disorder is selected from the groupconsisting of transplant rejection, a skin disorder, an allergy, asthmaand an autoimmune-mediated disease.
 41. The method according to claim36, wherein said neurodegenerative disorder is selected from the groupconsisting of Alzheimer's disease, a degenerative nerve disease,encephalitis, stroke, Parkinson's disease, amyotrophic lateralsclerosis, Huntington's disease and Pick's disease.
 42. The methodaccording to claim 36, further comprising subjecting said mammal in needthereof to a radiation therapy or chemotherapy regimen in combinationwith at least one cytostatic or cytotoxic agent.
 43. The methodaccording to claim 33, wherein said disease is selected from the groupconsisting of Type 1 diabetes, myocardial infarction, cardiovasculardisease, atherosclerosis, arrhythmias, obesity, an ocular disease and aninflammatory disease.
 44. The method according to claim 36, wherein saidcancer is selected from the group consisting of bladder cancer, breastcancer, colon cancer, kidney cancer, liver cancer, lung cancer, smallcell lung cancer, esophagus cancer, gall-bladder cancer, ovary cancer,pancreas cancer, stomach cancer, cervix cancer, thyroid cancer, prostatecancer, skin cancer, squamous cell carcinoma, leukaemia, acutelymphocitic leukaemia, acute lymphoblastic leukaemia, B-cell lymphoma,T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy celllymphoma, Burkett's lymphoma, acute myelogenous leukemias, chronicmyelogenous leukemias, myelodysplastic syndrome, promyelocyticleukaemia, fibrosarcoma, rhabdomyosarcoma, astrocytoma, neuroblastoma,glioma and schwannomas.